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  • Sympathetic Enhancement of Memory T Cell Homing and Hypertension Sensitization
    Circ. Res. (IF 15.862) Pub Date : 2020-01-13
    Liang Xiao; Luciana Do Carmo; Jason D Foss; Wei Chen; David G Harrison

    Rationale: Effector memory T lymphocytes (TEM cells) exacerbate hypertension in response to repeated hypertensive stimuli. These cells reside in the bone marrow for prolonged periods and can be reactivated upon re-exposure to the hypertensive stimulus.Objective: Because hypertension is associated with increased sympathetic outflow to the bone marrow, we hypothesized that sympathetic nerves regulate accumulation and reactivation of bone marrow residing hypertension-specific TEM cells.Methods and Results: Using unilateral superior cervical ganglionectomy in wild-type C57BL/6 mice, we showed that sympathetic nerves create a bone marrow environment that supports residence of hypertension-specific CD8+ T cells. These cells, defined by their proliferative response upon co-culture with dendritic cells from angiotensin II infused mice, were reduced in denervated compared to innervated bone of angiotensin II-infused mice. Adoptively transferred CD8+ T cells from angiotensin II-infused mice preferentially homed to innervated compared to denervated bone. In contrast, ovalbumin responsive T cells from OT-I mice did not exhibit this preferential homing. Increasing superior cervical ganglion activity by activating Gq-coupled DREADD (designer receptor exclusively activated by designer drug) augmented CD8+ TEM bone marrow accumulation. Adoptive transfer studies using mice lacking β2 adrenergic receptors (β2AR) indicate that β2AR in the bone marrow niche, rather than T cell β2AR is critical for TEM cell homing. Inhibition of global sympathetic outflow using Gi-coupled DREADD injected into the rostral ventrolateral medulla or treatment with a β2AR antagonist reduced hypertension specific CD8+ TEM cells in the bone marrow and reduced the hypertensive response to a subsequent response to low dose angiotensin II.Conclusions: Sympathetic nerves contribute to the homing and survival of hypertension-specific TEM cells in the bone marrow after they are formed in hypertension. Inhibition of sympathetic nerve activity and β2AR blockade reduces these cells and prevents the blood pressure elevation and renal inflammation upon re-exposure to hypertension stimuli.

    更新日期:2020-01-13
  • Three-Dimensional Imaging Provides Detailed Atherosclerotic Plaque Morphology and Reveals Angiogenesis after Carotid Artery Ligation
    Circ. Res. (IF 15.862) Pub Date : 2020-01-09
    Tobias Becher; Dario F Riascos-Bernal; Daniel J Kramer; Vanessa Almonte; Jingyi Chi; Tao Tong; Gustavo H Oliveira-Paula; Issam Koleilat; Wei Chen; Paul Cohen; Nicholas ES Sibinga

    Rationale: Remodeling of the vessel wall and the formation of vascular networks are dynamic processes that occur during mammalian embryonic development and in adulthood. Plaque development and excessive neointima formation are hallmarks of atherosclerosis and vascular injury. As our understanding of these complex processes evolves, there is a need to develop new imaging techniques to study underlying mechanisms.Objective: We used tissue clearing and light-sheet microscopy for three-dimensional (3D) profiling of the vascular response to carotid artery ligation and induction of atherosclerosis in mouse models.Methods and Results: Adipo-Clear and immunolabeling in combination with light-sheet microscopy were applied to image carotid arteries (CAs) and brachiocephalic arteries (BCAs), allowing for 3D reconstruction of vessel architecture. Entire 3D neointima formations with different geometries were observed within the CA and scored by volumetric analysis. Additionally, we identified a CD31-positive adventitial plexus after ligation of the CA that evolved and matured over time. We also used this method to characterize plaque extent and composition in the BCA of ApoE-deficient mice on high-fat diet. The plaques exhibited inter-animal differences in terms of plaque volume, geometry, and ratio of acellular core to plaque volume. A 3D reconstruction of the endothelium overlying the plaque was also generated.Conclusions: We present a novel approach to characterize vascular remodeling in adult mice using Adipo-Clear in combination with light-sheet microscopy. Our method reconstructs 3D neointima formation after arterial injury and allows for volumetric analysis of remodeling, in addition to revealing angiogenesis and maturation of a plexus surrounding the CA. This method generates complete 3D reconstructions of atherosclerotic plaques and uncovers their volume, geometry, acellular component, surface, and spatial position within the BCA. Our approach may be used in a number of mouse models of cardiovascular disease to assess vessel geometry and volume.

    更新日期:2020-01-09
  • BMX Represses Thrombin-PAR1-Mediated Endothelial Permeability and Vascular Leakage During Early Sepsis
    Circ. Res. (IF 15.862) Pub Date : 2020-01-08
    Zhao Li; Mingzhu Yin; Haifeng Zhang; Weiming Ni; Richard Pierce; Huanjiao Jenny Zhou; Wang Min

    Rationale: Bone marrow kinase on the X chromosome (BMX) is highly expressed in the arterial endothelium from the embryonic stage to the adult stage in mice. It is also expressed in microvessels and the lymphatics in response to pathological stimuli. However, its role in endothelial permeability and sepsis remains unknown.Objective: We aimed to delineate the function of BMX in thrombin-mediated endothelial permeability and the vascular leakage that occurs with sepsis in cecal ligation and puncture (CLP) models.Methods and Results: The CLP model was applied to wild-type and BMX knockout mice to induce sepsis. Meanwhile, the electric cell-substrate impedance sensing assay was used to detect trans-endothelial electrical resistance in vitro and the modified Miles assay was used to evaluate vascular leakage in vivo. We showed that BMX loss caused lung injury and inflammation in early CLP-induced sepsis. Disruption of BMX increased thrombin-mediated permeability in mice and cultured endothelial cells (ECs) by 2-3-fold. The expression of BMX in macrophages, neutrophils, platelets and lung epithelial cells was undetectable compared with that in ECs, indicating that endothelium dysfunction, rather than leukocyte and platelet dysfunction, was involved in vascular permeability and sepsis. Mechanistically, biochemical and cellular analyses demonstrated that BMX specifically repressed thrombin-protease-activated receptor 1 (PAR1) signaling in ECs by directly phosphorylating PAR1 and promoting its internalization and deactivation. Importantly, pre-treatment with the selective PAR1 antagonist SCH79797 rescued BMX loss-mediated endothelial permeability and pulmonary leakage in early CLP-induced sepsis.Conclusions: Acting as a negative regulator of PAR1, BMX promotes PAR1 internalization and signal inactivation through PAR1 phosphorylation. Moreover, BMX-mediated PAR1 internalization attenuates endothelial permeability to protect vascular leakage during early sepsis.

    更新日期:2020-01-08
  • Enhanced CaMKII-Dependent Late INa Induces Atrial Pro-Arrhythmic Activity in Patients with Sleep-Disordered Breathing
    Circ. Res. (IF 15.862) Pub Date : 2020-01-06
    Simon Lebek; Konstantin Pichler; Kathrin Reuthner; Maximilian Trum; Maria Tafelmeier; Julian Mustroph; d=Daniele camboni; Leopold Rupprecht; Christof Schmid; Lars S Maier; Michael Arzt; Stefan Wagner

    Rationale: Sleep-disordered breathing (SDB) is frequently associated with atrial arrhythmias. Increased Ca/calmodulin-dependent protein kinase II (CaMKII) activity has been previously implicated in atrial arrhythmogenesis.Objective: We hypothesized that CaMKII-dependent dysregulation of Na current (INa) may contribute to atrial pro-arrhythmic activity in SDB patients.Methods and Results: We prospectively enrolled 113 patients undergoing elective coronary artery bypass grafting for cross-sectional study and collected right atrial appendage biopsies. The presence of SDB (defined as apnea-hypopnea index, AHI {greater than or equal to}15/h) was assessed with a portable SDB monitor the night before surgery. Compared to 56 patients without SDB, patients with SDB (57) showed a significantly increased level of activated CaMKII. Patch clamp was used to measure INa. There was a significantly enhanced late INa but reduced peak INa due to enhanced steady-state inactivation in atrial myocytes of patients with SDB consistent with significantly increased CaMKII-dependent cardiac Na channel phosphorylation (NaV1.5, at serine 571, Western blotting). These gating changes could be fully reversed by acute CaMKII inhibition (AIP). As a consequence, we observed significantly more cellular afterdepolarizations and more severe premature atrial contractions (PACs) in atrial trabeculae of SDB patients, which could be blocked by either AIP or KN93. In multivariable linear regression models incorporating age, gender, body mass index, existing AF, existing heart failure, diabetes and creatinine levels, AHI was independently associated with increased CaMKII activity, enhanced late INa and correlated with PAC severity.Conclusions: In atrial myocardium of SDB patients, increased CaMKII-dependent phosphorylation of NaV1.5 results in dysregulation of INa with pro-arrhythmic activity that was independent from pre-existing co-morbidities. Inhibition of CaMKII may be useful for prevention or treatment of arrhythmias in SDB.

    更新日期:2020-01-06
  • Increased Drp1 Acetylation by Lipid Overload Induces Cardiomyocyte Death and Heart Dysfunction
    Circ. Res. (IF 15.862) Pub Date : 2020-01-03
    Qingxun Hu; Huiliang Zhang; Nicolas Gutierrez Cortes; Dan Wu; Pei Wang; Jing Zhang; Julie A Mattison; Eric Smith; Lisa F Bettcher; Mingyi Wang; Edward G Lakatta; Shey-Shing Sheu; Wang Wang

    Rationale: Lipid overload-induced heart dysfunction is characterized by cardiomyocyte death, myocardial remodeling, and compromised contractility, but the impact of excessive lipid supply on cardiac function remains poorly understood.Objective: To investigate the regulation and function of the mitochondrial fission protein dynamin-related protein 1 (Drp1) in lipid overload-induced cardiomyocyte death and heart dysfunction.Methods and Results: Mice fed a high-fat diet (HFD) developed signs of obesity and type II diabetes, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and hypertension. HFD for 18 weeks also induced heart hypertrophy, fibrosis, myocardial insulin resistance, and cardiomyocyte death. HFD stimulated mitochondrial fission in mouse hearts. Furthermore, HFD increased the protein level, phosphorylation (at the activating serine 616 site), oligomerization, mitochondrial translocation, and GTPase activity of Drp1 in mouse hearts, indicating that Drp1 was activated. Monkeys fed a diet high in fat and cholesterol for 2.5 years also exhibited myocardial damage and Drp1 activation in the heart. Interestingly, HFD decreased NAD+ levels and increased Drp1 acetylation in the heart. In adult cardiomyocytes, palmitate increased Drp1 acetylation, phosphorylation, and protein levels, and these increases were abolished by restoration of the decreased NAD+ level. Proteomics analysis and in vitro screening revealed that Drp1 acetylation at lysine 642 (K642) was increased by HFD in mouse hearts and by palmitate incubation in cardiomyocytes. The non-acetylated Drp1 mutation (K642R) attenuated palmitate-induced Drp1 activation, its interaction with voltage-dependent anion channel 1, mitochondrial fission, contractile dysfunction, and cardiomyocyte death.Conclusions: These findings uncover a novel mechanism that contributes to lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which, in turn, increased its activity and mitochondrial translocation, resulting in cardiomyocyte dysfunction and death. Thus, Drp1 may be a critical mediator of lipid overload-induced heart dysfunction as well as a potential target for therapy.

    更新日期:2020-01-04
  • In This Issue
    Circ. Res. (IF 15.862) Pub Date : 2020-01-02
    Ruth Williams

    In addition to excessive lipids in the blood, inflammation is a key driver of atherosclerosis. Indeed, plaques grow as a result of fatty deposits and the accumulation and proliferation of monocytes and macrophages in the vessel walls. In mice, such proliferation can be inhibited by the systemic administration of the immunosuppressive compound rapamycin. However, because such treatment can cause toxic side effects, researchers are investigating tissue-localized delivery methods. One such approach suggested by Boada and colleagues is to use rapamycin-loaded leukosomes—nanoparticles encapsulated in a lipid coating containing leukocyte membrane proteins. The coating enables the particles to mimic leukocyte homing such that they accumulate at atherosclerotic plaques. And now the team has shown that with a rapamycin payload, the particles reduce plaque macrophage proliferation better than systemic administration of the drug. Following 7 days of once-daily rapamycin-leukosome administration, plaque burden in atherosclerosis model mice was significantly lower than in control animals. Importantly, no toxicity was detected. These proof-of-principle results now set the stage for further testing in larger, clinically relevant animals, say the authors. In the body, essential fatty acids, such as those found in fish oils, are converted into specialized proresolving mediators (SPMs)—molecules that promote phagocytosis of dead cells and reduce inflammation. Whether taking such oils reduces vascular inflammation in people, however, is unclear. Some studies show the oils reduce inflammation, others show no effect. One problem is that there is no impartial measure of the clinical efficacy of such supplementation. Souza and colleagues, therefore, performed a double-blind, placebo-controlled study to determine the effects of marine oil supplementation on both SPM levels and immune cell function. Twenty-two volunteers were randomly assigned to receive placebo or 1 of 3 doses of marine oil. Blood samples from the subjects revealed a dose-dependent increase in SPMs that was significant in the 2 high-dose groups and peaked a few hours after dosing. The team went on to show that, in the high-dose blood samples, monocytes and neutrophils had increased phagocytic activity while leukocyte activation was decreased. These effects persisted after SPM levels returned to baseline. The results suggest SPMs are not only likely mediators of fatty acid-induced immune effects but that they could be useful efficacy indicators for future trials. A high level of triglycerides in the blood is a marker of cardiometabolic disease—a collection of symptoms including insulin resistance, obesity, dyslipidemia, and hypertension. However, this correlation does not occur in people of African ancestry. Indeed, black individuals may have apparently low triglyceride levels even when symptoms of cardiometabolic disease are present. To get to the bottom of this paradox, Chung and colleagues examined triglycerides in blood samples from black and white women to see if a specific subfraction of the lipoproteins—based on particle size—might correlate with symptoms. Women (122) of similar ages, body mass indices, and backgrounds had blood samples collected for insulin sensitivity tests and triglyceride measurements. The team found that while levels of large, medium, and small triglycerides were lower in blacks than whites regardless of insulin sensitivity, levels of very small triglycerides, which are known to be proatherogenic, did correlate with insulin sensitivity in both racial groups. The findings could not only form the basis of more accurate triglyceride tests for assessing cardiovascular disease severity in all races, but also highlight the potential importance of very small triglycerides in contributing to the progression of the condition.

    更新日期:2020-01-04
  • Meet the First Author
    Circ. Res. (IF 15.862) Pub Date : 2020-01-02

    Eric Schoger graduated from the University of Goettingen, Germany, with a BS in Molecular Medicine and MS in Cardiovascular Science and is currently a PhD student in Laura Zelarayan’s laboratory at the University Medical Center Goettingen. He joined Dr Zelarayan’s group during his undergraduate studies and investigated heart-specific regulators of Wnt/beta-catenin signaling in the embryonic and adult heart. For his master’s thesis, he joined Eric Olson’s laboratory at UT Southwestern to establish the cardiomyocyte-specific CRISPRa mouse model as a collaborative project. With this tool, he continues to activate gene programs to identify targets preventing heart failure progression. In his free time, he enjoys travelling, volunteers at the Red Cross, and tries to master his cooking skills. He can be found on Twitter @schogerandspice. Christian Boada is finishing up his PhD at Monterrey Tec in Mexico, where he also earned his BA in biosciences. His graduate work mainly focused on the application of biomimetic nanoparticles for the treatment of cardiovascular diseases. He is currently working as a postgraduate associate at Duke University, focusing on the application of biomimetic nanoparticles towards achieving long-term transplant tolerance. Christian’s research interests include nanotechonology, cardiovascular disease, and the investigation of immunological modulation by biomimetic particles. The manuscript in this issue represents the culmination of a long road that begun as a single experiment (inherited from a departing lab member) that was met with a lot of skepticism initially. In addition to his research, Christian enjoys exploring the intersection between art and science, as well as scientific illustration, providing cover images as well as figures for colleagues. Some of his work can be found at vizualscientist.com. He can be found on Twitter @VizualScientist. Dr Felipe Paredes grew up in the south of Chile, where he earned a BS in Biochemistry from the University of Conception. Later, he earned his PhD in Biochemistry from the University of Chile, focusing on understanding the role of endoplasmic reticulum oxidative stress in the regulation of mitochondrial function. In 2016, he moved to the US where he began working in the laboratory of Dr Alejandra San Martin in the Division of Cardiology at Emory University in Atlanta. During his tenure as a postdoctoral fellow, Dr Paredes has worked on elucidating the role of the mitochondrial protein Poldip2 in the regulation of bioenergetics and cell metabolism. He is passionate about the lab and his main research interest is in exploring the connection between proteasome function and the regulation of metabolism. Outside of the laboratory, Felipe loves to cook and spend time with his family and their new puppy, Picadillo. Dr Anja Karlstaedt is currently a Postdoctoral Research Fellow in the Division of Cardiology, McGovern Medical School at the University of Texas Health Science Center at Houston. Dr Karlstaedt earned her doctoral and medical degrees from the Charité – Universitätsmedizin Berlin in Germany, where she worked in the laboratories of Dr Hermann-Georg Holzhütter and Dr Vera Regitz-Zagrosek focusing on the metabolic stress response in the heart. She developed CardioNet (Karlstädt et al, 2012), the first genome-scale metabolic network of mammalian cardiac metabolism. In 2014, Dr Karlstaedt joined the laboratory of Dr Heinrich Taegtmeyer at McGovern Medical School, renowned for its expertise in cardiac metabolism and isolated working heart perfusions. Using systems biology approaches, she discovered that the oncometabolite D-2-hydroxyglutarate causes contractile dysfunction and epigenetic remodelling in the heart. With the support of an NIH Pathway to Independence Award (K99/R00), she wants to establish her own laboratory to study how metabolic stress derived from cancers drives the development of heart failure. Her goal is to develop therapeutic strategies that target the tumour while protecting the heart. In her spare time, Dr Karlstaedt enjoys playing the cello, learning new languages (she already speaks Danish and Japanese), and building robots using Raspberry Pi. Dr Patricia R. Souza earned her MS in 2012 from the Federal University of Minas Gerais/Brazil. In 2013, she started her PhD at WHRI/United Kingdom (mentor, Dr Mauro Perretti). Soon after earning her doctoral degree, she joined Dr Jesmond Dalli’s team to investigate the role of specialized proresolving mediators (SPM) in regulating innate and adaptive immune responses in rheumatoid arthritis and cardiovascular disease. Patricia loves the idea that one day she will be part of a discovery that will help transform the lives of people living with chronic inflammatory disorders. In the meantime, together with her beloved husband, she is focused on helping their daughter discover a new world every day. Dr Raquel Marques is a biochemist specializing in immunology. She earned her BS in 2007 from the Faculty of Science, University of Porto, Portugal. In 2014, she completed her PhD with a focus on the molecular and cellular immune mechanisms in the pathogenesis of Rabbit Haemorrhagic Disease at the Institute of Biomedical Sciences Abel Salazar, University of Porto, under the supervision of Dr Paula Ferreira Proença. She then moved to the Unit for Multidisciplinary Research in Biomedicine, University of Porto, where she focused on mechanisms involved in the resolution of inflammation and how these become disrupted in chronic inflammatory conditions. In 2016, she moved to London to join Dr Jesmond Dalli and his team at William Harvey Research Institute, the Barts and The London School of Medicine and Dentistry and Queen Mary College. Since then her work has been focused on the role of proresolving mediators in regulating both innate and adaptive immunity. Dr Stephanie T. Chung is originally from Kingston, Jamaica. She is a board-certified internist and pediatric endocrinologist, Co-Director of the Metabolic Research Unit in the Intramural Program of the National Institute of Diabetes, Digestive, and Kidney Diseases at the National Institutes of Health, and Adjunct Assistant Professor of Pediatrics at The George Washington University School of Medicine. She earned her M.B.B.S(Hons) from the University of the West Indies Medical School, completed her residency training at the University of Texas Medical Branch in Galveston, and her fellowship training at Baylor College of Medicine in Houston. Her combined clinical and research goals are to reduce diabetes health disparities across the lifespan by improving diabetes risk stratification and management, especially in women and underrepresented minority populations. Throughout her early career as a physician scientist, she has been a staunch advocate and mentor for aspiring young scientists from all backgrounds. Though often elusive, she strives to achieve work-life balance and enjoys running, hiking, and baking with her three children.

    更新日期:2020-01-04
  • CRISPR-Mediated Activation of Endogenous Gene Expression in the Postnatal Heart
    Circ. Res. (IF 15.862) Pub Date : 2019-11-15
    Eric Schoger; Kelli J. Carroll; Lavanya M. Iyer; John R. McAnally; Wei Tan; Ning Liu; Claudia Noack; Orr Shomroni; Gabriela Salinas; Julia Groß; Nicole Herzog; Shirin Doroudgar; Rhonda Bassel-Duby; Wolfram-H. Zimmermann; Laura C. Zelarayán

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    更新日期:2020-01-04
  • Rapamycin-Loaded Biomimetic Nanoparticles Reverse Vascular Inflammation
    Circ. Res. (IF 15.862) Pub Date : 2019-10-24
    Christian Boada; Assaf Zinger; Christopher Tsao; Picheng Zhao; Jonathan O. Martinez; Kelly Hartman; Tomoyuki Naoi; Roman Sukhoveshin; Manuela Sushnitha; Roberto Molinaro; Barry Trachtenberg; John P. Cooke; Ennio Tasciotti

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    更新日期:2020-01-04
  • 更新日期:2020-01-04
  • Glucose 6-Phosphate Accumulates via Phosphoglucose Isomerase Inhibition in Heart Muscle
    Circ. Res. (IF 15.862) Pub Date : 2019-11-08
    Anja Karlstaedt; Radhika Khanna; Manoj Thangam; Heinrich Taegtmeyer

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    更新日期:2020-01-04
  • Enriched Marine Oil Supplements Increase Peripheral Blood Specialized Pro-Resolving Mediators Concentrations and Reprogram Host Immune Responses
    Circ. Res. (IF 15.862) Pub Date : 2019-12-12
    Patricia R. Souza; Raquel M. Marques; Esteban A. Gomez; Romain A. Colas; Roberta De Matteis; Anne Zak; Mital Patel; David J. Collier; Jesmond Dalli

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    更新日期:2020-01-04
  • Triglyceride Paradox Is Related to Lipoprotein Size, Visceral Adiposity and Stearoyl-CoA Desaturase Activity in Black Versus White Women
    Circ. Res. (IF 15.862) Pub Date : 2019-10-18
    Stephanie T. Chung; Celeste K.L. Cravalho; Abby G. Meyers; Amber B. Courville; Shanna Yang; Nirupa Rachel Matthan; Lilian Mabundo; Maureen Sampson; Ronald Ouwerkerk; Ahmed M. Gharib; Alice H. Lichtenstein; Alan T. Remaley; Anne E. Sumner

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    更新日期:2020-01-04
  • Vitamin D, Marine n-3 Fatty Acids, and Primary Prevention of Cardiovascular Disease Current Evidence
    Circ. Res. (IF 15.862) Pub Date : 2020-01-02
    JoAnn E. Manson; Shari S. Bassuk; Nancy R. Cook; I-Min Lee; Samia Mora; Christine M. Albert; Julie E. Buring; for the VITAL Research Group

    Whether marine omega-3 fatty acid (n-3 FA) or vitamin D supplementation can prevent cardiovascular disease (CVD) in general populations at usual risk for this outcome is unknown. A major goal of VITAL (Vitamin D and Omega-3 Trial) was to fill this knowledge gap. In this article, we review the results of VITAL, discuss relevant mechanistic studies regarding n-3 FAs, vitamin D, and vascular disease, and summarize recent meta-analyses of the randomized trial evidence on these agents. VITAL was a nationwide, randomized, placebo-controlled, 2×2 factorial trial of marine n-3 FAs (1 g/d) and vitamin D3 (2000 IU/d) in the primary prevention of CVD and cancer among 25 871 US men aged ≥50 and women aged ≥55 years, including 5106 blacks. Median treatment duration was 5.3 years. Supplemental n-3 FAs did not significantly reduce the primary cardiovascular end point of major CVD events (composite of myocardial infarction, stroke, and CVD mortality; hazard ratio [HR], 0.92 [95% CI, 0.80–1.06]) but were associated with significant reductions in total myocardial infarction (HR, 0.72 [95% CI, 0.59–0.90]), percutaneous coronary intervention (HR, 0.78 [95% CI, 0.63–0.95]), and fatal myocardial infarction (HR, 0.50 [95% CI, 0.26–0.97]) but not stroke or other cardiovascular end points. For major CVD events, a treatment benefit was seen in those with dietary fish intake below the cohort median of 1.5 servings/wk (HR, 0.81 [95% CI, 0.67–0.98]) but not in those above (P interaction=0.045). For myocardial infarction, the greatest risk reductions were in blacks (HR, 0.23 [95% CI, 0.11–0.47]; P interaction by race, 0.001). Vitamin D supplementation did not reduce major CVD events (HR, 0.97 [95% CI, 0.85–1.12]) or other cardiovascular end points. Updated meta-analyses that include VITAL and other recent trials document coronary risk reduction from supplemental marine n-3 FAs but no clear CVD risk reduction from supplemental vitamin D. Additional research is needed to determine which individuals may be most likely to derive net benefit from supplementation.Clinical Trial Registration:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01169259.

    更新日期:2020-01-04
  • Role of Nitric Oxide Carried by Hemoglobin in Cardiovascular Physiology
    Circ. Res. (IF 15.862) Pub Date : 2019-10-08
    Richard T. Premont; James D. Reynolds; Rongli Zhang; Jonathan S. Stamler

    A continuous supply of oxygen is essential for the survival of multicellular organisms. The understanding of how this supply is regulated in the microvasculature has evolved from viewing erythrocytes (red blood cells [RBCs]) as passive carriers of oxygen to recognizing the complex interplay between Hb (hemoglobin) and oxygen, carbon dioxide, and nitric oxide—the three-gas respiratory cycle—that insures adequate oxygen and nutrient delivery to meet local metabolic demand. In this context, it is blood flow and not blood oxygen content that is the main driver of tissue oxygenation by RBCs. Herein, we review the lines of experimentation that led to this understanding of RBC function; from the foundational understanding of allosteric regulation of oxygen binding in Hb in the stereochemical model of Perutz, to blood flow autoregulation (hypoxic vasodilation governing oxygen delivery) observed by Guyton, to current understanding that centers on S-nitrosylation of Hb (ie, S-nitrosohemoglobin; SNO-Hb) as a purveyor of oxygen-dependent vasodilatory activity. Notably, hypoxic vasodilation is recapitulated by native S-nitrosothiol (SNO)–replete RBCs and by SNO-Hb itself, whereby SNO is released from Hb and RBCs during deoxygenation, in proportion to the degree of Hb deoxygenation, to regulate vessels directly. In addition, we discuss how dysregulation of this system through genetic mutation in Hb or through disease is a common factor in oxygenation pathologies resulting from microcirculatory impairment, including sickle cell disease, ischemic heart disease, and heart failure. We then conclude by identifying potential therapeutic interventions to correct deficits in RBC-mediated vasodilation to improve oxygen delivery—steps toward effective microvasculature-targeted therapies. To the extent that diseases of the heart, lungs, and blood are associated with impaired tissue oxygenation, the development of new therapies based on the three-gas respiratory system have the potential to improve the well-being of millions of patients.

    更新日期:2020-01-04
  • PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling
    Circ. Res. (IF 15.862) Pub Date : 2020-01-02
    Urszula Rykaczewska; Bianca E Suur; Samuel Röhl; Anton Razuvaev; Mariette Lengquist; Maria Sabater-Lleal; Sander W van der Laan; Clint L Miller; Robert C Wirka; Malin Kronqvist; Maria Gonzalez Diez; Mattias Vesterlund; Peter Gillgren; Jacob Odeberg; Jan HN Lindeman; Fabrizio Veglia; Steve E Humphries; Ulf de Faire; Damiano Baldassarre; Elena Tremoli; Janne Lehtiö; Göran K Hansson; Gabrielle Paulsson-Berne; Gerard Pasterkamp; Thomas Quertermous; Anders Hamsten; Per Eriksson; Ulf Hedin; Ljubica Matic

    Rationale: Proprotein convertase subtilisins/kexins (PCSKs) are a protease family with unknown functions in vasculature. Previously, we demonstrated PCSK6 upregulation in human atherosclerotic plaques associated with smooth muscle cells (SMCs), inflammation, extracellular matrix (ECM) remodeling and mitogens.Objective: Here, we applied a systems biology approach to gain deeper insights into the PCSK6 role in normal and diseased vessel wall.Methods and Results: Genetic analyses revealed association of intronic PCSK6 variant rs1531817 with maximum internal carotid intima-media thickness progression in high-cardiovascular risk subjects. This variant was linked with PCSK6 mRNA expression in healthy aortas and plaques, but also with overall plaque SMA+ cell content and pericyte fraction. Increased PCSK6 expression was found in several independent human cohorts comparing atherosclerotic lesions vs. healthy arteries, using transcriptomic and proteomic datasets. By immunohistochemistry, PCSK6 was localised to fibrous cap SMA+ cells and neovessels in plaques. In human, rat, and mouse intimal hyperplasia, PCSK6 was expressed by proliferating SMA+ cells and upregulated after 5 days in rat carotid balloon injury model, with positive correlation to PDGFB and MMP2/MMP14. Here, PCSK6 was shown to co-localise and co-interact with MMP2/MMP14 by in situ proximity ligation assay. Microarrays of carotid arteries from Pcsk6-/- vs. control mice revealed suppression of contractile SMC markers, ECM remodeling enzymes and cytokines/receptors. Pcsk6-/- mice showed reduced intimal hyperplasia response upon carotid ligation in vivo, accompanied by decreased MMP14 activation and impaired SMC outgrowth from aortic rings ex vivo. PCSK6 silencing in human SMCs in vitro lead to downregulation of contractile markers and increase in MMP2 expression. Conversely, PCSK6 overexpression increased PDGFBB-induced cell proliferation and particularly migration.Conclusions: PCSK6 is a novel protease that induces SMC migration in response to PDGFB, mechanistically via modulation of contractile markers and MMP14 activation. This study establishes PCSK6 as a key regulator of SMC function in vascular remodeling.

    更新日期:2020-01-02
  • Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa Driven Platelet Activation Via Protease Activated Receptor-1
    Circ. Res. (IF 15.862) Pub Date : 2019-12-20
    Tobias Petzold; Manuela Thienel; Lisa Kristina Dannenberg; Philipp Mourikis; Carolin helten; Aysel Ayhan; René M'Pembele; Alina Achilles; Kajetan Trojovsky; Daniel Konsek; Zhe Zang; Ron Regenauer; Joachim Pircher; Andreas Ehrlich; Enzo Lüsebrink; Leo Nicolai; Thomas Stocker; Richard Brandl; Franz Röschentaler; Jan Strecker; Inas Saleh; Michael Spannagl; Christoph Mayr; Herbert Schiller; Christian Jung; Norbert Gerdes; Till Hoffmann; Bodo Levkau; Thomas Hohlfeld; Tobias Zeus; Christian Schulz; Malte Kelm; Amin Polzin

    Rationale: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation (AF) treated with factor Xa (FXa) inhibitors including rivaroxaban (RIVA) compared to vitamin K antagonists. At the same time, low-dose RIVA has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease (CAD). Yet, the mechanisms underlying this reduction remain unknown.Objective: In this study we hypothesized, that RIVA's antithrombotic potential is linked to a hitherto unknown RIVA effect that impacts on platelet reactivity and arterial thrombosis.Methods and Results: In this study, we identified FXa as potent, direct agonist of the protease activated receptor-1 (PAR-1), leading to platelet activation and thrombus formation which can be inhibited by RIVA. We found that RIVA reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation (AF) patients on permanent RIVA treatment for stroke prevention, respective controls and patients with new onset AF prior to and after first intake of RIVA (time-series analysis) were recruited. Platelet aggregation responses as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material were attenuated by RIVA. We show that RIVA's antiplatelet effect is plasma dependent but independent of thrombin and RIVA's anticoagulatory capacity.Conclusions: Here we identified FXa as potent platelet agonist that acts through PAR1. Therefore, RIVA exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.

    更新日期:2019-12-20
  • Longitudinal RNA-seq Analysis of the Repeatability of Gene Expression and Splicing in Human Platelets Identifies A Platelet SELP Splice QTL
    Circ. Res. (IF 15.862) Pub Date : 2019-12-19
    Matthew Rondina; Deepak Voora; Lukas Simon; Hansjorg Schwertz; Julie Harper; Olivia Lee; Seema Bhatlekar; Qing Li; Alicia S Eustes; Emilie Montenont; Robert A Campbell; Neal Tolley; Yasuhiro Kosaka; Andrew Weyrich; Paul F Bray; Jesse W Rowley

    Rationale: Longitudinal studies are required to distinguish within versus between-individual variation, and repeatability of gene expression. They are uniquely positioned to decipher genetic signal from environmental noise, with potential application to gene variant and expression studies. However, longitudinal analyses of gene expression in healthy individuals—especially with regards to alternative splicing—are lacking for most primary cell types, including platelets.Objective: To assess repeatability of gene expression and splicing in platelets and use repeatability to identify novel platelet eQTLs and sQTLs.Methods and Results: We sequenced the transcriptome of platelets isolated repeatedly up to 4 years from healthy individuals. We examined within and between-individual variation and repeatability of platelet RNA-expression and exon skipping, a readily measured alternative splicing event. We find that platelet gene expression is generally stable between and within individuals over time—with the exception of a subset of genes enriched for the inflammation gene ontology. We show an enrichment among repeatable genes for associations with heritable traits, including known and novel platelet eQTLs. Several exon skipping events were also highly repeatable, suggesting heritable patterns of splicing in platelets. One of the most repeatable was exon 14 skipping of SELP. Accordingly, we identify rs6128 as a platelet sQTL and define an rs6128-dependent association between SELP exon 14 skipping and race. In vitro experiments demonstrate that this single nucleotide variant directly affects exon 14 skipping, and changes the ratio of transmembrane versus soluble P-selectin protein production.Conclusions: We conclude that the platelet transcriptome is generally stable over 4-years. We demonstrate the use of repeatability of gene expression and splicing to identify novel platelet eQTLs and sQTLs. rs6128 is a platelet sQTL that alters SELP exon 14 skipping and soluble versus transmembrane P-selectin protein production.

    更新日期:2019-12-19
  • Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress
    Circ. Res. (IF 15.862) Pub Date : 2019-12-19
    Anna E Dikalova; Arvind K Pandey; Liang Xiao; Liaisan Arslanbaeva; Tatiana Sidorova; Marcos G Lopez; Frederic T Billings IV; Eric Verdin; Johan Auwerx; David G Harrison; Sergey I Dikalov

    Rationale: Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction contributes to hypertension, but specific mechanisms are unclear. The mitochondrial deacetylase Sirt3 is critical in the regulation of metabolic and antioxidant functions which are associated with hypertension, and cardiovascular disease risk factors diminish Sirt3 level.Objective: We hypothesized that reduced Sirt3 expression contributes to vascular dysfunction in hypertension but increased Sirt3 protects vascular function and decreases hypertension.Methods and Results: To test the therapeutic potential of targeting Sirt3 expression we developed new transgenic mice with global Sirt3 overexpression (Sirt3OX) which protects from endothelial dysfunction, vascular oxidative stress and hypertrophy, attenuates angiotensin II- and DOCA-salt induced hypertension. Global Sirt3 depletion in Sirt3-/- mice results in oxidative stress due to SOD2 hyperacetylation, increases HIF1α, reduces endothelial cadherin, stimulates vascular hypertrophy, increases vascular permeability and vascular inflammation (p65, caspase 1, VCAM, ICAM and MCP1), increases inflammatory cell infiltration in the kidney, reduces telomerase expression, and accelerates vascular senescence and age-dependent hypertension; conversely, increased Sirt3 expression in Sirt3OX mice prevents these deleterious effects. The clinical relevance of Sirt3 depletion was confirmed in arterioles from human mediastinal fat in patients with essential hypertension showing a 40% decrease in vascular Sirt3, coupled with Sirt3 dependent 3-fold increases in SOD2 acetylation, NfKB activity, VCAM, ICAM and MCP1 levels in hypertensive subjects compared with normotensive subjects.Conclusions: We suggest that Sirt3 depletion in hypertension promotes endothelial dysfunction, vascular hypertrophy, vascular inflammation and end-organ damage. Our data support a therapeutic potential of targeting Sirt3 expression in vascular dysfunction and hypertension.

    更新日期:2019-12-19
  • Duration and Life-Stage of Antibiotic Use and Risks of All-Cause and Cause-Specific Mortality: A Prospective Cohort Study
    Circ. Res. (IF 15.862) Pub Date : 2019-12-17
    Yoriko Heianza; Wenjie Ma; Xiang Li; Yin Cao; Andrew Chan; Eric B Rimm; Frank B Hu; Kathryn Rexrode; JoAnn E Manson; Lu Qi

    Rationale: The overuse of antibiotics has been an important clinical issue, and antibiotic exposure is linked to alterations in gut microbiota, which has been related to risks of various chronic diseases such as cardiovascular disease (CVD) and cancer. Also, duration of antibiotic exposure may be a risk factor of premature death.Objective: We investigated associations of life-stage and duration of antibiotic use during adulthood with risks of all-cause and cause-specific mortality.Methods and Results: This prospective cohort study included 37,516 women aged {greater than or equal to}60 y who were free of CVD or cancer from the Nurses' Health Study. Participants reported a total amount of time they used antibiotics (none, <15 days, 15 days to <2 months, or {greater than or equal to}2 months) in the middle- (age 40-59) and late adulthood (age 60 or older). We estimated hazard ratios (HRs) for all-cause mortality and deaths from CVD or cancer over 10 years according to duration of antibiotic use. During 355,918 person-years of follow-up, we documented 4536 deaths from any cause (including 728 cardiovascular deaths and 1206 cancer deaths). As compared to women who did not use antibiotics, those who used them for {greater than or equal to}2 months in late adulthood had increased risks of all-cause mortality (HR 1.16; 95% CI: 1.01, 1.33) and cardiovascular mortality (HR 1.49; [95% CI: 1.04, 2.13]), but not cancer mortality (HR 0.85 [0.65, 1.12]) after adjustment for chronic metabolic diseases, antibiotic use during middle adulthood, indication for use, demographic factors, and lifestyle/dietary factors. The association was more evident among women who also used antibiotics in middle-adulthood than among those who did not use during this life-stage.Conclusions: Long-term use of antibiotics in late adulthood may be a risk factor for all-cause and cardiovascular mortality. The unfavorable effect of antibiotic exposure for subsequent risks of deaths due to chronic diseases needs to be considered.

    更新日期:2019-12-18
  • A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyte
    Circ. Res. (IF 15.862) Pub Date : 2019-12-11
    Julie Heffler, Parisha P Shah, Patrick Robison, Sai Phyo, Kimberly Veliz, Keita Uchida, Alexey Bogush, Joshua Rhoades, Rajan Jain, Benjamin L Prosser

    Rationale: Mechanical forces are transduced to nuclear responses via the Linkers of the Nucleo- and Cytoskeleton (LINC) complex, which couples the cytoskeleton to the nuclear lamina and associated chromatin. While disruption of the LINC complex can cause cardiomyopathy, the relevant interactions that bridge the nucleo- to cytoskeleton are poorly understood in the cardiomyocyte, where cytoskeletal organization is unique. Further, while microtubules and desmin intermediate filaments associate closely with cardiomyocyte nuclei, the importance of these interactions is unknown.Objective: Here we sought to determine how cytoskeletal interactions with the LINC complex regulate nuclear homeostasis in the cardiomyocyte.Methods and Results: To this end, we acutely disrupted the LINC complex, microtubules, actin, and intermediate filaments and assessed the consequences on nuclear morphology and genome organization in rat ventricular cardiomyocytes via a combination of super-resolution imaging, biophysical, and genomic approaches. We find that a balance of dynamic microtubules and desmin intermediate filaments is required to maintain nuclear shape and the fidelity of the nuclear envelope and lamina. Upon depletion of desmin (or nesprin-3, its binding partner in the LINC complex), polymerizing microtubules collapse the nucleus and drive infolding of the nuclear membrane. This results in DNA damage, a loss of genome organization, and broad transcriptional changes. The collapse in nuclear integrity is concomitant with compromised contractile function and may contribute to the pathophysiological changes observed in desmin-related myopathies.Conclusions: Disrupting the tethering of desmin to the nucleus results in a loss of nuclear homeostasis and rapid alterations to cardiomyocyte function. Our data suggest that a balance of forces imposed by intermediate filaments and microtubules is required to maintain nuclear structure and genome organization in the cardiomyocyte.

    更新日期:2019-12-11
  • Age-Associated Mitochondrial Dysfunction Accelerates Atherogenesis
    Circ. Res. (IF 15.862) Pub Date : 2019-12-09
    Daniel J Tyrrell, Muriel Blin, Jianrui Song, Sherri Wood, Min Zhang, Daniel A Beard, Daniel Goldstein

    Rationale: Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known.Objective: To determine if vascular aging prior to the induction of hyperlipidemia enhances atherogenesis.Methods and Results: We analyzed the aortas of young and aged normolipidemic wild type (WT), disease free mice and found that aging led to elevated IL-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged WT mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis.Conclusions: Prior to hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.

    更新日期:2019-12-11
  • Interleukin-10 Deficiency Alters Endothelial Progenitor Cell -Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase Enrichment
    Circ. Res. (IF 15.862) Pub Date : 2019-12-09
    Yujia Yue, Chunlin Wang, Cindy L Benedict, Grace Huang, May M Truongcao, Rajika Roy, Maria Cimini, Venkata Naga Srikanth Garikipati, Zhongjian Cheng, Walter J Koch, Raj Kishore

    Rationale: Systemic inflammation compromises the reparative properties of Endothelial Progenitor Cell (EPC) and their exosomes on myocardial repair, while the underlying mechanism of loss of function of exosomes from inflamed EPCs is still obscure.Objective: To determine the mechanisms of Interleukin-10 (IL-10) deficient-EPC-derived exosome dysfunction in myocardial repair and to investigate if modification of specific exosome cargo can rescue reparative activity.Methods and Results: Using interleukin-10 (IL-10) knockout (KO) mice mimicking systemic inflammation condition, we compared therapeutic effect and protein cargo of exosomes isolated from wild type EPC and IL-10KO-EPC. In a mouse model of myocardial infarction (MI) WT-EPC-Exo treatment significantly improved left ventricle cardiac function, inhibited cell apoptosis, reduced MI scar size and promoted post-MI neovascularization, while IL-10KO-EPC-Exo treatment showed diminished and opposite effects. Mass spectrometry analysis revealed WT-EPC-Exo and IL-10KO-EPC-Exo contain different protein expression pattern. Amongst differentially expressed proteins, Integrin Linked Kinase (ILK) was highly enriched in both IL-10KO-EPC-Exo as well as TNFα treated Mouse Cardiac Endothelial Cell derived exosomes (MCEC+TNFα-Exo). ILK enriched exosomes activated NFκB pathway and NFkB-dependent gene transcription in recipient endothelial cells and this effect was partly attenuated though ILK knockdown in exosomes. Intriguingly, ILK knockdown in IL-10KO-EPC-Exo significantly rescued their reparative dysfunction in myocardial repair, improved left ventricle cardiac function, reduced MI scar size and enhanced post-MI neovascularization in MI mouse model.Conclusions: IL-10 deficiency/inflammation alters EPC derived exosome function, content and therapeutic effect on myocardial repair by upregulating ILK enrichment in exosomes and ILK-mediated activation of NFĸB pathway in recipient cells while ILK knockdown in exosomes attenuates NFĸB activation and reduces inflammatory response. Our study provides new understanding of how inflammation may alters stem cell-exosome mediated cardiac repair and identifies ILK as a target kinase for improving progenitor cell exosome-based cardiac therapies.

    更新日期:2019-12-09
  • Coronary Disease Associated Gene TCF21 Inhibits Smooth Muscle Cell Differentiation by Blocking the Myocardin-Serum Response Factor Pathway
    Circ. Res. (IF 15.862) Pub Date : 2019-12-09
    Manabu Nagao, Qing Lyu, Quanyi Zhao, Robert C Wirka, Joetsaroop Bagga, Trieu Nguyen, Paul Cheng, Juyong Brian Kim, Milos Pjanic, Joseph M Miano, Thomas Quertermous

    Rationale: The gene encoding transcription factor TCF21 has been linked to coronary artery disease (CAD) risk by human genome wide association studies (GWAS) in multiple racial ethnic groups. In murine models, Tcf21 is required for phenotypic modulation of smooth muscle cells (SMC) in atherosclerotic tissues and promotes a fibroblast phenotype in these cells. In humans, TCF21 expression inhibits risk for CAD. The molecular mechanism by which TCF21 regulates SMC phenotype is not known.Objective: To better understand how TCF21 affects SMC phenotype, we sought to investigate the possible mechanisms by which it regulates the lineage determining myocardin (MYOCD)-serum response factor (SRF) pathway.Methods and Results: Modulation of TCF21 expression in HCASMC revealed that TCF21 suppresses a broad range of SMC markers, as well as key SMC transcription factors MYOCD and SRF, at the RNA and protein level. We conducted chromatin immunoprecipitation (ChIP)-sequencing to map SRF binding sites in HCASMC, showing that binding is colocalized in the genome with TCF21, including at a novel enhancer in the SRF gene, and at the MYOCD gene promoter. In vitro genome editing indicated that the SRF enhancer CArG box regulates transcription of the SRF gene, and mutation of this conserved motif in the orthologous mouse SRF enhancer revealed decreased SRF expression in aorta and heart tissues. Direct TCF21 binding and transcriptional inhibition at co-localized sites were established by reporter gene transfection assays. Chromatin immunoprecipitation and protein co-immunoprecipitation studies provided evidence that TCF21 blocks MYOCD and SRF association by direct TCF21-MYOCD interaction.Conclusions: These data indicate that TCF21 antagonizes the MYOCD-SRF pathway through multiple mechanisms, further establishing a role for this CAD associated gene in fundamental SMC processes and indicating the importance of smooth muscle response to vascular stress and phenotypic modulation of this cell type in CAD risk.

    更新日期:2019-12-09
  • Integrative Omics Approach to Identifying Genes Associated with Atrial Fibrillation
    Circ. Res. (IF 15.862) Pub Date : 2019-12-05
    Biqi Wang, Kathryn Lunetta, Josée Dupuis, Steven A Lubitz, Ludovic Trinquart, Lixia Yao, Patrick T Ellinor, Emelia J Benjamin, Honghuang Lin

    Rationale: Genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with atrial fibrillation (AF). However, these loci explain only a small proportion of AF heritability.Objective: To develop an approach to identify additional AF-related genes by integrating multiple omics data.Methods and Results: Three types of omics data were integrated: 1) summary statistics from the AFGen 2017 GWAS; 2) a whole blood epigenome-wide association study (EWAS) of AF; and 3) a whole blood transcriptome-wide association study (TWAS) of AF. The variant-level GWAS results were collapsed into gene-level associations using fast set-based association analysis (fastBAT). The CpG-level EWAS results were also collapsed into gene-level associations by an adapted SNP-set Kernel Association Test (SKAT) approach. Both GWAS and EWAS gene-based associations were then meta-analyzed with TWAS using a fixed-effects model weighted by the sample size of each data set. A tissue-specific network was subsequently constructed using the Network-wide association study (NetWAS). The identified genes were then compared with the AFGen 2018 GWAS that contained twice the number of AF cases compared to AFGen 2017 GWAS. We observed that the multi-omics approach identified many more relevant AF-related genes than using AFGen 2018 GWAS alone (1931 vs. 206 genes). Many of these genes are involved in the development and regulation of heart and muscle related biological processes. Moreover, the gene set identified by multi-omics approach explained much more AF variance than those identified by GWAS alone (10.4% vs 3.5%).Conclusions: We developed a strategy to integrate multiple omics data to identify AF-related genes. Our integrative approach may be useful to improve the power of traditional GWAS, which might be particularly useful for rare traits and diseases with limited sample size.

    更新日期:2019-12-05
  • Loss of Endothelial FTO Antagonizes Obesity-Induced Metabolic and Vascular Dysfunction
    Circ. Res. (IF 15.862) Pub Date : 2019-12-05
    Nenja Krüger, Lauren A Biwer, Miranda E Good, Claire A Ruddiman, Abigail G Wolpe, Leon J DeLalio, Sara Murphy, Edgar H Macal, Louis Ragolia, Vlad Serbulea, Angela K Best, Norbert Leitinger, Thurl E Harris, Swapnil K Sonkusare, Axel Gödecke, Brant E Isakson

    Rationale: Increasing prevalence of obesity and its associated risk with cardiovascular diseases demands a better understanding of the contribution of different cell types within this complex disease for developing new treatment options. Previous studies could prove a fundamental role of the Fat mass and obesity associated gene (Fto) within obesity; however, its functional role within different cell types is less understood.Objective: We identify endothelial FTO as a previously unknown central regulator of both obesity-induced metabolic and vascular alterations.Methods and Results: We generated endothelial Fto-deficient mice and analyzed the impact of obesity on those mice. While the loss of endothelial FTO did not influence the development of obesity and dyslipidemia, it protected mice from high fat diet (HFD)- induced glucose intolerance and insulin resistance by increasing AKT phosphorylation in endothelial cells and skeletal muscle. Furthermore, loss of endothelial FTO prevented the development of obesity-induced hypertension by preserving myogenic tone in resistance arteries. In Fto-deficient arteries, microarray analysis identified upregulation of Lipocalin-type prostaglandin D synthase (L-Pgds) with significant increases in prostaglandin D2 (PGD2) levels. Blockade of PGD2-synthesis inhibited the myogenic tone protection in resistance arteries of endothelial Fto-deficient mice on HFD; conversely, direct addition of PGD2 rescued myogenic tone in HFD-fed control mice. Myogenic tone was increased in obese human arteries with FTO inhibitors or PGD2 application.Conclusions: These data identify endothelial FTO as a previously unknown regulator in the development of obesity-induced metabolic and vascular changes, which is independent of its known function in regulation of obesity.

    更新日期:2019-12-05
  • Activated Endothelial TGFβ1 Signaling Promotes Venous Thrombus Non-Resolution in Mice Via Endothelin-1: Potential Role for Chronic Thromboembolic Pulmonary Hypertension
    Circ. Res. (IF 15.862) Pub Date : 2019-11-21
    Magdalena Ludmila Bochenek, Christiane Leidinger, Nico S Rosinus, Rajinikanth Gogiraju, Stefan Guth, Lukas Hobohm, Kerstin Jurk, Eckhard Mayer, Thomas Münzel, Mareike Lankeit, Markus Bosmann, Stavros Konstantinides, Katrin Schäfer

    Rationale: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by defective thrombus resolution, pulmonary artery obstruction and vasculopathy. Transforming growth factor-beta (TGFβ) signaling mutations have been implicated in pulmonary arterial hypertension, whereas TGFβ's role in the pathophysiology of CTEPH is unknown.Objective: To determine whether defective TGFβ signaling in endothelial cells contributes to thrombus non-resolution and fibrosis.Methods and Results: Venous thrombosis was induced by inferior vena cava ligation in mice with genetic deletion of TGFβ1 in platelets (Plt.TGFβ-KO) or TGFβ type II receptors in endothelial cells (End.TGFβRII-KO). Pulmonary endarterectomy specimens from CTEPH patients were analyzed using immunohistochemistry. Primary human and mouse endothelial cells were studied using confocal microscopy, quantitative PCR and western blot. Absence of TGFβ1 in platelets did not alter platelet number or function, but was associated with faster venous thrombus resolution, whereas endothelial TGFβRII deletion resulted in larger, more fibrotic and higher vascularized venous thrombi. Increased circulating active TGFβ1 levels, endothelial TGFβRI/ALK1 and TGFβRI/ALK5 expression were detected in End.TGFβRII-KO mice, and activated TGFβ signaling was present in vessel-rich areas of CTEPH specimens. CTEPH-ECs and murine endothelial cells lacking TGFβRII simultaneously expressed endothelial and mesenchymal markers and transcription factors regulating endothelial-to-mesenchymal transition, similar to TGFβ1-stimulated endothelial cells. Mechanistically, increased endothelin-1 levels were detected in TGFβRII-KO endothelial cells, murine venous thrombi or endarterectomy specimens and plasma of CTEPH patients, and endothelin-1 overexpression was prevented by inhibition of ALK5, and to a lesser extent of ALK1. ALK5 inhibition and endothelin receptor antagonization inhibited mesenchymal lineage conversion in TGFβ1-exposed human and murine endothelial cells and improved venous thrombus resolution and pulmonary vaso-occlusions in End.TGFβRII-KO mice.Conclusions: Endothelial TGFβ1 signaling via type I receptors and endothelin-1 contribute to mesenchymal lineage transition and thrombofibrosis, which were prevented by blocking endothelin receptors. Our findings may have relevant implications for the prevention and management of CTEPH.

    更新日期:2019-11-21
  • Functional Screening of Candidate Causal Genes for Insulin Resistance in Human Preadipocytes and Adipocytes
    Circ. Res. (IF 15.862) Pub Date : 2019-11-19
    Zhifen Chen, Haojie Yu, Xu Shi, Curtis R Warren, Luca A Lotta, Max Friesen, Torsten Meissner, Claudia Langenberg, Martin Wabitsch, Nick Wareham, Mark D Benson, Robert E Gerszten, Chad A. Cowan

    Rationale: Genome-wide association studies (GWAS) have identified genetic loci associated with insulin resistance (IR) but pinpointing the causal genes of a risk locus has been challenging.Objective: To identify candidate causal genes for IR, we screened regional and biologically plausible genes (16 in total) near the top ten IR-loci in risk-relevant cell types, namely preadipocytes and adipocytes.Methods and Results: We generated 16 human Simpson-Golabi-Behmel syndrome preadipocyte knockout lines (SGBS-KO) by lentivirus-mediated CRISPR/Cas9 system. We evaluated each gene knockout by screening IR-relevant phenotypes in the three insulin-sensitizing mechanisms, including adipogenesis, lipid metabolism and insulin signaling. We performed genetic analyses to evaluate whether candidate genes prioritized by our in vitro studies were eQTL genes in human subcutaneous adipose tissue, and were associated with risk of IR, type 2 diabetes (T2D) and cardiovascular diseases (CVD). We further validated the functions of three new adipose IR genes by phenotypic rescue in the SGBS-KO cell lines. Results: Twelve genes, PPARG, IRS-1, FST, PEPD, PDGFC, MAP3K1, GRB14, ARL15, ANKRD55, RSPO3, COBLL1 and LYPLAL1, showed diverse phenotypes in the three insulin-sensitizing mechanisms, and the first seven of these genes could affect all the three mechanisms. Five of six eQTL genes are among the top candidate causal genes and the abnormal expression levels of these genes (IRS-1, GRB14, FST, PEPD and PDGFC) in human SAT could be associated with increased risk of IR, T2D and CVD. Phenotypic rescue of FST, PEPD and PDGFC in the SGBS-KO lines confirmed their function in adipose IR.Conclusions: Twelve genes showed diverse phenotypes indicating differential roles in insulin sensitization, suggesting mechanisms bridging the association of their genomic loci with IR. We prioritized PPARG, IRS-1, GRB14, MAP3K1, FST, PEPD and PDGFC as top candidate genes. Our work points to novel roles for FST, PEPD and PDGFC in adipose tissue, with consequences for cardiometabolic diseases.

    更新日期:2019-11-19
  • Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis
    Circ. Res. (IF 15.862) Pub Date : 2019-11-11
    Julia Ritterhoff, Sara Young, Outi Villet, Dan Shao, Fausto Carnevale Neto, Lisa F Bettcher, Yun-Wei A Hsu, Stephen C Kolwicz, Daniel Raftery, Rong Tian

    Rationale: Hypertrophied hearts switch from mainly using fatty acids (FA) to an increased reliance on glucose for energy production. It has been shown that preserving fatty acid oxidation (FAO) prevents the pathological shift of substrate preference, preserves cardiac function and energetics, and reduces cardiomyocyte (CM) hypertrophy during cardiac stresses. However, it remains elusive if substrate metabolism regulates CM hypertrophy directly or via a secondary effect of improving cardiac energetics.Objective: The goal of this study was to determine the mechanisms of how preservation of FAO prevents the hypertrophic growth of cardiomyocytes.Methods and Results: We cultured adult rat CMs in a medium containing glucose and mixed chain fatty acids and induced pathological hypertrophy by phenylephrine (PE). PE-induced hypertrophy was associated with increased glucose consumption and higher intracellular aspartate levels, resulting in increased synthesis of nucleotides, RNA and proteins. These changes could be prevented by increasing FAO via deletion of acetyl-CoA-carboxylase 2 (ACC2) in PE stimulated CMs and in pressure overload induced cardiac hypertrophy in vivo. Furthermore, aspartate supplementation was sufficient to reverse the anti-hypertrophic effect of ACC2 deletion demonstrating a causal role of elevated aspartate level in CM hypertrophy. 15N and 13C stable isotope tracing revealed that glucose but not glutamine contributed to increased biosynthesis of aspartate which supplied nitrogen for nucleotide synthesis during CM hypertrophy.Conclusions: Our data show that increased glucose consumption is required to support aspartate synthesis that drives the increase of biomass during cardiac hypertrophy. Preservation of FAO prevents the shift of metabolic flux into the anabolic pathway and maintains catabolic metabolism for energy production, thus preventing cardiac hypertrophy and improving myocardial energetics.

    更新日期:2019-11-11
  • In This Issue
    Circ. Res. (IF 15.862) Pub Date : 2019-11-07
    Ruth Williams

    Cardiomyocytes derived from human pluripotent stem cells (hPSC) are a valuable resource for drug discovery, disease modeling, and more. But, generally speaking, such cells remain immature compared with their natural adult counterparts, limiting their use. A variety of methods exist to promote maturation, but there is currently no consensus on the best way to assess such maturity—some researchers use electrophysiology, others transcriptome data and so on. Cai and colleagues have, therefore, established a straightforward, yet comprehensive, mass spectrometry approach. The method combines analysis of a subset of intact proteins with an unbiased screen of digested peptide fragments. The team used the method to examine early and late-stage maturation of cardiomyocytes derived from embryonic and induced hPSCs, validating their findings against cells from mouse hearts. For the intact protein analysis, sarcomeres were isolated from cell samples, allowing identification of the major sarcomeric proteins and their maturation-related post-translational modifications, while the unbiased screen enabled identification of both known and novel maturation markers. The work, thus, not only provides a handy tool for assessing maturity, but also a set of maturity markers for cross-reference. Natriuretic peptide (NP) is a hormone that promotes sodium excretion via the urine as well as other physiological effects. It is secreted from the heart’s atrial cardiac muscle, and low levels of NP are associated with risk of cardiometabolic diseases, including hypertension and diabetes. Being black is also a risk factor for such conditions, and a study of middle-aged and older people revealed that blacks tend to have lower NP levels than whites. Whether this difference is apparent in young healthy individuals before such diseases emerge, however, was unknown. To find out, Patel et al examined the levels of NP and factors that regulate the hormone in a cohort of young adults, half of whom were black. The team showed that, on average, blacks had significantly lower levels of NP and higher levels of factors that downregulate the hormone than whites. Analysis of heart tissue collected from deceased organ donors also revealed that proteins involved in the processing and clearance of NP tended to be more abundant in black individuals. The results sow the seeds for future investigations into whether NP levels directly influence cardiometabolic disease, and if so, whether interventions to boost the hormone could be of clinical benefit. Leptin—a hormone released from fatty tissue—increases metabolism and blood pressure and reduces appetite. In obese individuals, however, despite high levels of leptin, metabolism and appetite may be unaltered, yet hypertension may still develop. Leptin’s effects on appetite and metabolism are mediated in the brain, while its effects on blood pressure are thought to be mediated elsewhere. Indeed, Shin and colleagues suspected the carotid body (CB)—a cluster of cells in the neck that detect blood levels of oxygen and other substances and communicate the information to the brain via the carotid sinus nerve (CSN). The CB has abundant expression of a leptin receptor and, moreover, leptin has been shown to increase CSN firing. Shin and colleagues now show that, indeed, infusions of leptin into mice increased hypertension in the animals only when the CSN was intact. They also showed that this effect was dependent on the ion channel Trpm7, which is abundant in the CB. Furthermore, inhibition of Trpm7 prevented the leptin-induced hypertension. Together, the results begin to explain why, in obese individuals, leptin still induces hypertension when the hormone’s other effects are diminished. And they suggest that inhibition of Trpm7 could be a way to treat hypertension, particularly in obese individuals.

    更新日期:2019-11-08
  • Meet the First Authors
    Circ. Res. (IF 15.862) Pub Date : 2019-11-07

    Dr Nirav Patel earned his MD from the Baroda Medical College, India. After graduation, he started working as a postdoctoral clinical research fellow under the supervision of Dr Pankaj Arora at the University of Alabama at Birmingham (UAB), whose words, “As a practicing clinician, you can certainly make a meaningful impact to the well-being of a few families in your career, but as a physician-scientist, you can change lives of millions,” still ring in his ears every day. Nirav’s research is focused on understanding the response of the natriuretic peptide system to physiological and pharmacological perturbations and gaining mechanistic insights into natriuretic peptide deficiency states, such as obesity. Nirav is currently a physician-scientist medicine/cardiology trainee at UAB and relishing his clinical medicine years, which he describes as far less strenuous than his postdoc. Outside of work, Nirav enjoys time with his wife and likes to travel around the world. Dr Ram Prasad is a Scientist-I in the lab of Dr Maria Grant in the Department of Ophthalmology and Visual Sciences at the University of Alabama at Birmingham (UAB). After completing his PhD at Jamia Millia Islamia, New Delhi, India, he joined the Department of Dermatology at UAB in 2010, where he worked on various cellular and molecular mechanism associated with the development and progression of different cancers. His research mainly focused on dissecting the molecular and cellular mechanisms linking prevention/intervention. In 2018, he joined Dr Grant’s lab in order to gain deeper insights into diabetes and diabetic microvascular complications. For him, scientific research is the answer to all biological puzzles. His life’s goal is to produce meaningful scientific research and help to improve the quality of life of the various patient populations. Outside the lab, he likes to spend time with his family and participate in indoor and outdoor activities, like swimming, pool table, table tennis, soccer, biking, and sightseeing. Dr Mi-Kyung Shin is a research associate in the Department of Medicine, Johns Hopkins University. She earned her MS and PhD from Inha University in South Korea. Since 2010, she has been working with Dr Polotsky, who is focused on the effects of intermittent hypoxia on lipid and glucose metabolism and the pathogenesis of obstructive sleep apnea. Mi-Kyung focuses on the role of carotid bodies and sympathetic nervous system in metabolic and cardiovascular complications of sleep-disordered breathing. Together, with Dr Polotosky, Mi-Kyung has begun to explore new pathways to develop treatment for obese patients with poorly controlled hypertension, diabetes, and sleep apnea. In the lab, she likes to help and communicate with colleagues. And, outside the lab, she likes reading, cooking, and volunteering with her church. Her favorite book is The Chronicles of Narnia, by C.S. Lewis, and her motto is, “There is no failure except in no longer trying.” Dr Chien-Jung Lin is currently an interventional cardiology fellow at Washington University in St. Louis. He received his MD from National Taiwan University. His PhD studies with Dr Matthew Scott at Stanford University focused on epigenetic factors in cardiac development. He then moved to Washington University for clinical training in internal medicine and cardiology. As part of the physician-scientist training pathway, he spent a year in the laboratory of Dr Robert Mecham. Initially aiming to study the source of elastic recoil after percutaneous intervention, he stumbled upon an unexpected heterogeneity in the cellular contribution to arterial elastic laminae, which formed the basis of the study published in this issue. After finishing his year of clinical interventional cardiology training, he will return to the bench to complete research training. His long-term goal is a career as a physician-scientist in interventional cardiology, translating knowledge of disease mechanisms to clinical applications. When not placing stents, seeing patients, or working in the lab, he enjoys hiking and spending time with family. Dr Marc Clement earned his PhD in 2014 from Paris Denis Diderot University (mentor, Dr Giuseppina Caligiuri), where he studied immune cell interactions in the setting of chronic inflammatory diseases. His PhD was supported by a scholarship from Région Paris Île-de-France (CORRDIM). Previously, Dr Clement earned a BS in Biomedical Research from Ecole Supérieure des Techniques de Biologie Appliquée (ESTBA, Paris, France), and an MS in Biology from the Ecole Pratique des Hautes Etudes (EPHE, Paris, France). In 2015, he was awarded the Prix Aguirre-Basualdo/Robin, Medicine, from the Chancellerie des Universités de Paris. He worked as a postdoctoral fellow in Dr Ziad Mallat’s lab at the University of Cambridge (UK), Department of Cardiovascular Medicine until 2018. In 2019, he obtained a Grant from the “Fondation pour la recherche médicale” to study vascular inflammation and kidney diseases in the Laboratory for Vascular Translational Science (LVTS, INSERM U1148, Paris, France). His research focuses on pro- and anti-inflammatory processes mediating kidney fibrosis. He is particularly interested in studying the mechanisms linking inflammatory-mediated tissue damages and glomerulosclerosis.

    更新日期:2019-11-08
  • An Unbiased Proteomics Method to Assess the Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes
    Circ. Res. (IF 15.862) Pub Date : 2019-10-01
    Wenxuan Cai, Jianhua Zhang, Willem J. de Lange, Zachery R. Gregorich, Hannah Karp, Emily T. Farrell, Stanford D. Mitchell, Trisha Tucholski, Ziqing Lin, Mitch Biermann, Sean J. McIlwain, J. Carter Ralphe, Timothy J. Kamp, Ying Ge

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    更新日期:2019-11-08
  • Race, Natriuretic Peptides, and High-Carbohydrate Challenge
    Circ. Res. (IF 15.862) Pub Date : 2019-10-06
    Nirav Patel, Griffin K. Russell, Kiran Musunuru, Orlando M. Gutierrez, Ganesh Halade, Vasundhara Kain, Wenjian Lv, Sumanth D. Prabhu, Kenneth B. Margulies, Thomas P. Cappola, Garima Arora, Thomas J. Wang, Pankaj Arora

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    更新日期:2019-11-08
  • Bone Marrow-Derived Cells Restore Functional Integrity of the Gut Epithelial and Vascular Barriers in a Model of Diabetes and ACE2 Deficiency
    Circ. Res. (IF 15.862) Pub Date : 2019-10-15
    Yaqian Duan, Ram Prasad, Dongni Feng, Eleni Beli, Sergio Li Calzi, Ana Leda F. Longhini, Regina Lamendella, Jason L. Floyd, Mariana Dupont, Sunil K. Noothi, Gopalkrishna Sreejit, Baskaran Athmanathan, Justin Wright, Amanda R. Jensen, Gavin Y. Oudit, Troy A. Markel, Prabhakara R. Nagareddy, Alexander G. Obukhov, Maria B. Grant

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    更新日期:2019-11-08
  • Leptin Induces Hypertension Acting on Transient Receptor Potential Melastatin 7 Channel in the Carotid Body
    Circ. Res. (IF 15.862) Pub Date : 2019-09-23
    Mi-Kyung Shin, Candela Caballero Eraso, Yun-Ping Mu, Chenjuan Gu, Bonnie H.Y. Yeung, Lenise J. Kim, Xiao-Ru Liu, Zhi-Juan Wu, Omkar Paudel, Luis E. Pichard, Machiko Shirahata, Wan-Yee Tang, James S.K. Sham, Vsevolod Y. Polotsky

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    更新日期:2019-11-08
  • Heterogeneous Cellular Contributions to Elastic Laminae Formation in Arterial Wall Development
    Circ. Res. (IF 15.862) Pub Date : 2019-10-08
    Chien-Jung Lin, Marius C. Staiculescu, Jie Z. Hawes, Austin J. Cocciolone, Bridget M. Hunkins, Robyn A. Roth, Chieh-Yu Lin, Robert P. Mecham, Jessica E. Wagenseil

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    更新日期:2019-11-08
  • Impaired Autophagy in CD11b+ Dendritic Cells Expands CD4+ Regulatory T Cells and Limits Atherosclerosis in Mice
    Circ. Res. (IF 15.862) Pub Date : 2019-10-15
    Marc Clement, Juliette Raffort, Fabien Lareyre, Dimitrios Tsiantoulas, Stephen Newland, Yuning Lu, Leanne Masters, James Harrison, Svetlana Saveljeva, Marcella K.L. Ma, Maria Ozsvar-Kozma, Brian Y.H. Lam, Giles S.H. Yeo, Christoph J. Binder, Arthur Kaser, Ziad Mallat

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    更新日期:2019-11-08
  • miRNA-Mediated Suppression of a Cardioprotective Cardiokine as a Novel Mechanism Exacerbating Post-MI Remodeling by Sleep Breathing Disorders
    Circ. Res. (IF 15.862) Pub Date : 2019-11-07
    Yunhui Du, Xiao Wang, Lin-Yi Li, Wenjing Hao, Huina Zhang, Yu Li, YanWen Qin, Shaoping Nie, Theodore Christopher, Bernard Lopez, Yajing Wang, Wayne Bond Lau, Yong-Xiang Wei, Xin-Liang L Ma

    Rationale: Obstructive sleep apnea (OSA), a sleep breathing disorder in which chronic intermittent hypoxia (CIH) is the primary pathology, is associated with multiple cardiovascular diseases. However, whether and how CIH may affect cardiac remodeling following myocardial infarction (MI) remains unknown.Objective: To determine whether CIH exposure at different periods of MI may exacerbate post-MI heart failure and to identify the mechanisms underlying CIH-exacerbated post-MI remodeling.Methods and Results: Adult male mice were subjected to MI (4 weeks) with and without CIH (4 or 8 weeks). CIH prior to MI (CIH+MI) had no significant effect upon post-MI remodeling. However, double CIH exposure (CIH+MI+CIH) or CIH only during the MI period (MI+CIH) significantly exacerbated pathologic remodeling and reduced survival rate. Mechanistically, CIH activated TGF-beta/Smad signaling and enhanced cardiac epithelial to mesenchymal transition, markedly increasing post-MI cardiac fibrosis. Transcriptome analysis revealed that, among 15 genes significantly downregulated (MI+CIH versus MI), Ctrp9 (a novel cardioprotective cardiokine) was one of the most significantly inhibited genes. Rt-PCR/Western analysis confirmed that cardiomyocyte Ctrp9 expression was significantly reduced in MI+CIH mice. RNA-seq, Rt-PCR, and dual-luciferase reporter assays identified that miR-214-3p is a novel Ctrp9 targeting miRNA. Its upregulation is responsible for Ctrp9 gene suppression in MI+CIH. Finally, AAV9-mediated cardiac-specific Ctrp9 overexpression or rCTRP9 administration inhibited TGF-beta/Smad and Wnt/β-catenin pathways, attenuated interstitial fibrosis, improved cardiac function, and enhanced survival rate in MI+CIH animals.Conclusions: This study provides the first evidence that MI+CIH upregulates miR-214-3p, suppresses cardiac CTRP9 expression, and exacerbates cardiac remodeling, suggesting that CTRP9 may be a novel therapeutic target against pathologic remodeling in MI patients with OSA.

    更新日期:2019-11-07
  • Monogenic and Polygenic Contributions to Atrial Fibrillation Risk: Results from a National Biobank
    Circ. Res. (IF 15.862) Pub Date : 2019-11-06
    Seung Hoan Choi, Sean J Jurgens, Lu-Chen Weng, James Paul Pirruccello, Carolina Roselli, Mark Chaffin, Christina Lee, Amelia Weber Hall, Amit V Khera, Kathryn Lunetta, Steven A Lubitz, Patrick T Ellinor

    Rationale: Genome-wide association studies have identified over 100 genetic loci for atrial fibrillation (AF); recent work described an association between loss-of-function (LOF) variants in TTN and early-onset AF.Objective: We sought to determine the contribution of rare and common genetic variation to AF risk in the general population.Methods and Results: The UK Biobank is a population-based study of 500,000 individuals including a subset with genome-wide genotyping and exome sequencing. In this case-control study, we included AF cases and controls of genetically determined white-European ancestry; analyses were performed using a logistic mixed-effects model adjusting for age, sex, the first 4 principal components of ancestry, empirical relationships and case-control imbalance. An exome wide, gene-based burden analysis was performed to examine the relationship between AF and rare, high-confidence LOF variants in genes with {greater than or equal to} 10 LOF carriers. A polygenic risk score (PRS) for AF was estimated using the LDpred algorithm. We then compared the contribution of AF PRS and LOF variants to AF risk. The study included 1,546 AF cases and 41,593 controls. In an analysis of 9,099 genes with sufficient LOF variant carriers, a significant association between AF and rare LOF variants was observed in a single gene, TTN (OR 2.71, P=2.50x10-8). The association with AF was more significant (OR 6.15, P=3.26x10-14) when restricting to LOF variants located in exons highly expressed in cardiac tissue (TTNLOF). Overall, 0.44% of individuals carried TTNLOF variants, of whom 14% had AF. Among individuals in the highest 0.44% of the AF PRS, only 9.3% had AF. In contrast, an AF PRS explained 4.7% of the variance in AF susceptibility, while TTNLOF variants only accounted for 0.2%.Conclusions: Both monogenic and polygenic factors contribute to AF risk in the general population. While monogenic TTNLOF variants confer a substantial AF penetrance, polygenic risk explains a larger proportion of genetic susceptibility to AF.

    更新日期:2019-11-06
  • Blood Pressure Normalization-Independent Cardioprotective Effects of Endogenous, Physical Activity-Induced Alpha Calcitonin Gene-Related Peptide (αCGRP) in Chronically Hypertensive Mice
    Circ. Res. (IF 15.862) Pub Date : 2019-10-31
    Tom Skaria, Katharyn Mitchell, Olga Vogel, Thomas Wälchli, Max Gassmann, Johannes Vogel

    Rationale: α-calcitonin gene related peptide (αCGRP), one of the strongest vasodilators, is cardioprotective in hypertension by reducing the elevated blood pressure (BP).Objective: However, we hypothesize that endogenous, physical activity-induced αCGRP has BP-independent cardioprotective effects in chronic hypertension. MMethods and Results: Chronically hypertensive (one-kidney-one-clip surgery) WT and αCGRP-/- sedentary or voluntary wheel running mice were treated with vehicle, αCGRP, or the αCGRP receptor antagonist CGRP8-37. Cardiac function and myocardial phenotype were evaluated echocardiographically and by molecular, cellular and histological analysis, respectively. BP was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological remodeling and heart failure in sedentary, chronically hypertensive WT mice. In these mice, voluntary wheel running significantly improved myocardial phenotype and function, which was abolished by CGRP8-37 treatment. In αCGRP-/- mice, αCGRP treatment, in contrast to voluntary wheel running, improved myocardial phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary, murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-dependent blunting of pathological cardiac remodeling.Conclusions: Endogenous, physical activity-induced αCGRP has BP-independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger hypertensive patients.

    更新日期:2019-11-01
  • Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.
    Circ. Res. (IF 15.862) Pub Date : 2016-12-03
    Gregory T Jones,Gerard Tromp,Helena Kuivaniemi,Solveig Gretarsdottir,Annette F Baas,Betti Giusti,Ewa Strauss,Femke N G Van't Hof,Thomas R Webb,Robert Erdman,Marylyn D Ritchie,James R Elmore,Anurag Verma,Sarah Pendergrass,Iftikhar J Kullo,Zi Ye,Peggy L Peissig,Omri Gottesman,Shefali S Verma,Jennifer Malinowski,Laura J Rasmussen-Torvik,Kenneth M Borthwick,Diane T Smelser,David R Crosslin,Mariza de Andrade,Evan J Ryer,Catherine A McCarty,Erwin P Böttinger,Jennifer A Pacheco,Dana C Crawford,David S Carrell,Glenn S Gerhard,David P Franklin,David J Carey,Victoria L Phillips,Michael J A Williams,Wenhua Wei,Ross Blair,Andrew A Hill,Thodor M Vasudevan,David R Lewis,Ian A Thomson,Jo Krysa,Geraldine B Hill,Justin Roake,Tony R Merriman,Grzegorz Oszkinis,Silvia Galora,Claudia Saracini,Rosanna Abbate,Raffaele Pulli,Carlo Pratesi,Athanasios Saratzis,Ana R Verissimo,Suzannah Bumpstead,Stephen A Badger,Rachel E Clough,Gillian Cockerill,Hany Hafez,D Julian A Scott,T Simon Futers,Simon P R Romaine,Katherine Bridge,Kathryn J Griffin,Marc A Bailey,Alberto Smith,Matthew M Thompson,Frank M van Bockxmeer,Stefan E Matthiasson,Gudmar Thorleifsson,Unnur Thorsteinsdottir,Jan D Blankensteijn,Joep A W Teijink,Cisca Wijmenga,Jacqueline de Graaf,Lambertus A Kiemeney,Jes S Lindholt,Anne Hughes,Declan T Bradley,Kathleen Stirrups,Jonathan Golledge,Paul E Norman,Janet T Powell,Steve E Humphries,Stephen E Hamby,Alison H Goodall,Christopher P Nelson,Natzi Sakalihasan,Audrey Courtois,Robert E Ferrell,Per Eriksson,Lasse Folkersen,Anders Franco-Cereceda,John D Eicher,Andrew D Johnson,Christer Betsholtz,Arno Ruusalepp,Oscar Franzén,Eric E Schadt,Johan L M Björkegren,Leonard Lipovich,Anne M Drolet,Eric L Verhoeven,Clark J Zeebregts,Robert H Geelkerken,Marc R van Sambeek,Steven M van Sterkenburg,Jean-Paul de Vries,Kari Stefansson,John R Thompson,Paul I W de Bakker,Panos Deloukas,Robert D Sayers,Seamus C Harrison,Andre M van Rij,Nilesh J Samani,Matthew J Bown

    RATIONALE Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE To identify additional AAA risk loci using data from all available genome-wide association studies. METHODS AND RESULTS Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. CONCLUSIONS The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

    更新日期:2019-11-01
  • Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy.
    Circ. Res. (IF 15.862) Pub Date : 2006-12-13
    Cissy Chenyi Zhou,Shakil Ahmad,TieJuan Mi,Lingwei Xia,Shahrzad Abbasi,Peter W Hewett,ChunXiao Sun,Asif Ahmed,Rodney E Kellems,Yang Xia

    Maternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system.

    更新日期:2019-11-01
  • Calcium-independent negative inotropy by beta-myosin heavy chain gene transfer in cardiac myocytes.
    Circ. Res. (IF 15.862) Pub Date : 2007-03-17
    Todd J Herron,Rene Vandenboom,Ekaterina Fomicheva,Lakshmi Mundada,Terri Edwards,Joseph M Metzger

    Increased relative expression of the slow molecular motor of the heart (beta-myosin heavy chain [MyHC]) is well known to occur in many rodent models of cardiovascular disease and in human heart failure. The direct effect of increased relative beta-MyHC expression on intact cardiac myocyte contractility, however, is unclear. To determine the direct effects of increased relative beta-MyHC expression on cardiac contractility, we used acute genetic engineering with a recombinant adenoviral vector (AdMYH7) to genetically titrate beta-MyHC protein expression in isolated rodent ventricular cardiac myocytes that predominantly expressed alpha-MyHC (fast molecular motor). AdMYH7-directed beta-MyHC protein expression and sarcomeric incorporation was observed as soon as 1 day after gene transfer. Effects of beta-MyHC expression on myocyte contractility were determined in electrically paced single myocytes (0.2 Hz, 37 degrees C) by measuring sarcomere shortening and intracellular calcium cycling. Gene transfer-based replacement of alpha-MyHC with beta-MyHC attenuated contractility in a dose-dependent manner, whereas calcium transients were unaffected. For example, when beta-MyHC expression accounted for approximately 18% of the total sarcomeric myosin, the amplitude of sarcomere-length shortening (nanometers, nm) was depressed by 42% (151.0+/-10.7 [control] versus 87.0+/-5.4 nm [AdMYH7 transduced]); and genetic titration of beta-MyHC, leading to 38% beta-MyHC content, attenuated shortening by 57% (138.9+/-13.0 versus 59.7+/-7.1 nm). Maximal isometric cross-bridge cycling rate was also slower in AdMYH7-transduced myocytes. Results indicate that small increases of beta-MyHC expression (18%) have Ca2+ transient-independent physiologically relevant effects to decrease intact cardiac myocyte function. We conclude that beta-MyHC is a negative inotrope among the cardiac myofilament proteins.

    更新日期:2019-11-01
  • Divergent biophysical defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia.
    Circ. Res. (IF 15.862) Pub Date : 2007-12-01
    Thao P Nguyen,Dao W Wang,Thomas H Rhodes,Alfred L George

    Mutations in SCN5A encoding the principal Na+ channel alpha-subunit expressed in human heart (Na(V)1.5) have recently been linked to an inherited form of dilated cardiomyopathy with atrial and ventricular arrhythmia. We compared the biophysical properties of 2 novel Na(V)1.5 mutations associated with this syndrome (D2/S4--R814W; D4/S3--D1595H) with the wild-type (WT) channel using heterologous expression in cultured tsA201 cells and whole-cell patch-clamp recording. Expression levels were similar among WT and mutant channels, and neither mutation affected persistent sodium current. R814W channels exhibited prominent and novel defects in the kinetics and voltage dependence of activation characterized by slower rise times and a hyperpolarized conductance-voltage relationship resulting in an increased "window current." This mutant also displayed enhanced slow inactivation and greater use-dependent reduction in peak current at fast pulsing frequencies. By contrast, D1595H channels exhibited impaired fast inactivation characterized by slower entry into the inactivated state and a hyperpolarized steady-state inactivation curve. Our findings illustrate the divergent biophysical defects caused by 2 different SCN5A mutations associated with familial dilated cardiomyopathy. Retrospective review of the published clinical data suggested that cardiomyopathy was not common in the family with D1595H, but rather sinus bradycardia was the predominant clinical finding. However, for R814W, we speculate that an increased window current coupled with enhanced slow inactivation and rate-dependent loss of channel availability provided a unique substrate predisposing myocytes to disordered Na+ and Ca2+ homeostasis leading to myocardial dysfunction.

    更新日期:2019-11-01
  • Regulatory role of G protein-coupled estrogen receptor for vascular function and obesity.
    Circ. Res. (IF 15.862) Pub Date : 2009-01-31
    Elvira Haas,Indranil Bhattacharya,Eugen Brailoiu,Marlen Damjanović,G Cristina Brailoiu,Xin Gao,Laurence Mueller-Guerre,Nicole A Marjon,André Gut,Roberta Minotti,Matthias R Meyer,Kerstin Amann,Emerita Ammann,Ana Perez-Dominguez,Michele Genoni,Deborah J Clegg,Nae J Dun,Thomas C Resta,Eric R Prossnitz,Matthias Barton

    We found that the selective stimulation of the intracellular, transmembrane G protein-coupled estrogen receptor (GPER), also known as GPR30, acutely lowers blood pressure after infusion in normotensive rats and dilates both rodent and human arterial blood vessels. Stimulation of GPER blocks vasoconstrictor-induced changes in intracellular calcium concentrations and vascular tone, as well as serum-stimulated cell proliferation of human vascular smooth muscle cells. Deletion of the GPER gene in mice abrogates vascular effects of GPER activation and is associated with visceral obesity. These findings suggest novel roles for GPER in protecting from cardiovascular disease and obesity.

    更新日期:2019-11-01
  • The LIM protein leupaxin is enriched in smooth muscle and functions as an serum response factor cofactor to induce smooth muscle cell gene transcription.
    Circ. Res. (IF 15.862) Pub Date : 2008-05-24
    Liisa J Sundberg-Smith,Laura A DiMichele,Rebecca L Sayers,Christopher P Mack,Joan M Taylor

    Leupaxin is a LIM domain-containing adapter protein belonging to the paxillin family that has been previously reported to be preferentially expressed in hematopoietic cells. Herein, we identified leupaxin in a screen for focal adhesion kinase binding partners in aortic smooth muscle, and we show that leupaxin is enriched in human and mouse vascular smooth muscle and that leupaxin expression is dynamically regulated during development. In addition, our studies reveal that leupaxin can undergo cytoplasmic/nuclear shuttling and functions as an serum response factor cofactor in the nucleus. We found that leupaxin forms a complex with serum response factor and associates with CArG-containing regions of smooth muscle promoters and that ectopic expression of leupaxin induces smooth muscle marker gene expression in both 10T1/2 cells and rat aortic smooth muscle cells. Subsequent studies indicated that enhanced focal adhesion kinase activity (induced by fibronectin or expression of constitutively active focal adhesion kinase) attenuates the nuclear accumulation of leupaxin and limits the ability of leupaxin to enhance serum response factor-dependent gene transcription. Thus, these studies indicate that modulation of the subcellular localization of serum response factor cofactors is 1 mechanism by which extracellular matrix-dependent signals may regulate phenotypic switching of smooth muscle cells.

    更新日期:2019-11-01
  • Meet the First Authors.
    Circ. Res. (IF 15.862) Pub Date : 2019-02-15

    更新日期:2019-11-01
  • Finding the rhythm of sudden cardiac death: new opportunities using induced pluripotent stem cell-derived cardiomyocytes.
    Circ. Res. (IF 15.862) Pub Date : 2015-06-06
    Karim Sallam,Yingxin Li,Philip T Sager,Steven R Houser,Joseph C Wu

    Sudden cardiac death is a common cause of death in patients with structural heart disease, genetic mutations, or acquired disorders affecting cardiac ion channels. A wide range of platforms exist to model and study disorders associated with sudden cardiac death. Human clinical studies are cumbersome and are thwarted by the extent of investigation that can be performed on human subjects. Animal models are limited by their degree of homology to human cardiac electrophysiology, including ion channel expression. Most commonly used cellular models are cellular transfection models, which are able to mimic the expression of a single-ion channel offering incomplete insight into changes of the action potential profile. Induced pluripotent stem cell-derived cardiomyocytes resemble, but are not identical, adult human cardiomyocytes and provide a new platform for studying arrhythmic disorders leading to sudden cardiac death. A variety of platforms exist to phenotype cellular models, including conventional and automated patch clamp, multielectrode array, and computational modeling. Induced pluripotent stem cell-derived cardiomyocytes have been used to study long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and other hereditary cardiac disorders. Although induced pluripotent stem cell-derived cardiomyocytes are distinct from adult cardiomyocytes, they provide a robust platform to advance the science and clinical care of sudden cardiac death.

    更新日期:2019-11-01
  • J-Waves in Epicardial Electrograms Can Guide Ablation of Arrhythmogenic Substrates.
    Circ. Res. (IF 15.862) Pub Date : 2019-01-18
    Bastiaan J Boukens,Tobias Opthof,Ruben Coronel

    更新日期:2019-11-01
  • Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression.
    Circ. Res. (IF 15.862) Pub Date : 2015-07-04
    Philipp Du Bois,Cristina Pablo Tortola,Doerte Lodka,Melanie Kny,Franziska Schmidt,Kunhua Song,Sibylle Schmidt,Rhonda Bassel-Duby,Eric N Olson,Jens Fielitz

    RATIONALE Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) expression, which may involve protein kinase D1 (PKD1). OBJECTIVE To elucidate the molecular mechanism of Ang II-induced skeletal muscle wasting. METHODS AND RESULTS A cDNA expression screen identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1 promoter. TFEB played a key role in regulating Ang II-induced skeletal muscle atrophy by transcriptional control of MuRF1 via conserved E-box elements. Inhibiting TFEB with small interfering RNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deacetylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking PKD1 in skeletal myocytes were resistant to Ang II-induced muscle wasting. CONCLUSION We propose that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.

    更新日期:2019-11-01
  • Individualized Knowledge Graph: A Viable Informatics Path to Precision Medicine.
    Circ. Res. (IF 15.862) Pub Date : 2017-04-01
    Peipei Ping,Karol Watson,Jiawei Han,Alex Bui

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  • Leptin Activates Trpm7 Channels in the Carotid Body As a Mechanism of Obesity-Related Hypertension.
    Circ. Res. (IF 15.862) Pub Date : 2019-11-08
    Fang Zheng,Shengyu Mu,Nancy J Rusch

    更新日期:2019-11-01
  • A Proteomic Perspective on Cardiomyocyte Maturation.
    Circ. Res. (IF 15.862) Pub Date : 2019-11-08
    Naoto Muraoka,Bingyun Sun,Charles E Murry

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  • Common variants in myocardial ion channel genes modify the QT interval in the general population: results from the KORA study.
    Circ. Res. (IF 15.862) Pub Date : 2005-03-05
    Arne Pfeufer,Shapour Jalilzadeh,Siegfried Perz,Jakob C Mueller,Martin Hinterseer,Thomas Illig,Mahmut Akyol,Cornelia Huth,Andreas Schöpfer-Wendels,Bernhard Kuch,Gerhard Steinbeck,Rolf Holle,Michael Näbauer,H-Erich Wichmann,Thomas Meitinger,Stefan Kääb

    Altered myocardial repolarization is one of the important substrates of ventricular tachycardia and fibrillation. The influence of rare gene variants on repolarization is evident in familial long QT syndrome. To investigate the influence of common gene variants on the QT interval we performed a linkage disequilibrium based SNP association study of four candidate genes. Using a two-step design we analyzed 174 SNPs from the KCNQ1, KCNH2, KCNE1, and KCNE2 genes in 689 individuals from the population-based KORA study and 14 SNPs with results suggestive of association in a confirmatory sample of 3277 individuals from the same survey. We detected association to a gene variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele, P=0.0002) and observed weaker association to a variant upstream of the KCNE1 gene (rs727957, +1.2 ms/allele, P=0.0051). In addition we detected association to two SNPs in the KCNH2 gene, the previously described K897T variant (rs1805123, -1.9 ms/allele, P=0.0006) and a gene variant that tags a different haplotype in the same block (rs3815459, +1.7 ms/allele, P=0.0004). The analysis of additive effects by an allelic score explained a 10.5 ms difference in corrected QT interval length between extreme score groups and 0.951 of trait variance (P<0.00005). These results confirm previous heritability studies indicating that repolarization is a complex trait with a significant heritable component and demonstrate that high-resolution SNP-mapping in large population samples can detect and fine map quantitative trait loci even if locus specific heritabilities are small.

    更新日期:2019-11-01
  • Impaired KCNQ1-KCNE1 and phosphatidylinositol-4,5-bisphosphate interaction underlies the long QT syndrome.
    Circ. Res. (IF 15.862) Pub Date : 2005-03-05
    Kyu-Ho Park,Julien Piron,Shehrazade Dahimene,Jean Mérot,Isabelle Baró,Denis Escande,Gildas Loussouarn

    Nearly a hundred different KCNQ1 mutations have been reported as leading to the cardiac long QT syndrome, characterized by prolonged QT interval, syncopes, and sudden death. We have previously shown that phosphatidylinositol-4,5-bisphosphate (PIP2) regulates the KCNQ1-KCNE1 complex. In the present study, we show that PIP2 affinity is reduced in three KCNQ1 mutant channels (R243H, R539W, and R555C) associated with the long QT syndrome. In giant excised patches, direct application of PIP2 on the cytoplasmic face of the three mutant channels counterbalances the loss of function. Reintroduction of a positive charge by application of methanethiosulfonate ethylammonium on the cytoplasmic face of R555C mutant channels also restores channel activity. The channel affinity for a soluble analog of PIP2 is decreased in the three mutant channels. By using a model that describes the KCNQ1-KCNE1 channel behavior and by fitting the relationship between the kinetics of deactivation and the current amplitude obtained in whole-cell experiments, we estimated the PIP2 binding and dissociation rates on wild-type and mutant channels. The dissociation rate of the three mutants was higher than for the wild-type channel, suggesting a decreased affinity for PIP2. PIP2 binding was magnesium-dependent, and the PIP2-dependent equilibrium constant in the absence of magnesium was higher with the wild-type than with the mutant channels. Altogether, our data suggest that a reduced PIP2 affinity of KCNQ1 mutants can lead to the long QT syndrome.

    更新日期:2019-11-01
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