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  • Angiotensin Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System
    Circ. Res. (IF 15.862) Pub Date : 2020-04-08
    Mahmoud Gheblawi; Kaiming Wang; Anissa Viveiros; Quynh Nguyen; Jiu-Chang Zhong; Anthony J Turner; Mohan K Raizada; Maria B Grant; Gavin Y Oudit

    Angiotensin-converting enzyme (ACE2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system (RAS), facilitator of amino acid transport, and the SARS-CoV and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has

  • COVID-19 and the Heart
    Circ. Res. (IF 15.862) Pub Date : 2020-04-07
    Akbarshakh Akhmerov; Eduardo Marban

    Infection with the novel coronavirus, SARS-CoV-2, produces a clinical syndrome known as COVID-19. When severe, COVID-19 is a systemic illness characterized by hyperinflammation, cytokine storm and elevations of cardiac injury biomarkers. Here we review what is known about the pathophysiology of COVID-19, its cardiovascular manifestations, and emerging therapeutic prospects. In this rapidly moving field

  • Identification of Functional Variant Enhancers Associated with Atrial Fibrillation
    Circ. Res. (IF 15.862) Pub Date : 2020-04-06
    Antoinette Felicia van Ouwerkerk; Fernanda Bosada; Jia Liu; Juan Zhang; Karel van Duijvenboden; Mark Chaffin; Nathan Tucker; Daniël A Pijnappels; Patrick T Ellinor; Phil Barnett; Antoine AF de Vries; Vincent M Christoffels

    Rationale: Genome-wide association studies (GWAS) have identified a large number of common variants (single nucleotide polymorphisms) associated with atrial fibrillation (AF). These variants are located mainly in non-coding regions of the genome and likely include variants that modulate the function of transcriptional regulatory elements (REs) such as enhancers. However, the actual REs modulated by

  • Catecholamines Induce Trained Immunity In Monocytes In Vitro and In Vivo
    Circ. Res. (IF 15.862) Pub Date : 2020-04-03
    Charlotte Dinka Christina Corinna van der Heijden; Laszlo Groh; Samuel T Keating; Charlotte Kaffa; Marlies P Noz; Simone Kersten; Antonius E van Herwaarden; Alexander Hoischen; Leo AB Joosten; Henri JLM Timmers; Mihai G Netea; Niels P Riksen

    Rationale: Exposure to high catecholamine levels is associated with inflammatory changes of myeloid cells and atherosclerosis, but the underlying mechanisms are only partly understood.Objective: To investigate whether the pro-inflammatory effects of noradrenaline and adrenaline can in part be explained by the induction of an immunological memory in innate immune cells, termed 'trained immunity'.Methods

  • Endothelial Palmitoylation Cycling Coordinates Vessel Remodeling in Peripheral Artery Disease
    Circ. Res. (IF 15.862) Pub Date : 2020-04-01
    Xiaochao Wei; Sangeeta Adak; Mohamed Adel Zayed; Li Yin; Chu Feng; Sarah L Speck; Rahul S Kathayat; Qiang Zhang; Bryan C Dickinson; Clay F Semenkovich

    Rationale: Peripheral artery disease, common in metabolic syndrome and diabetes, responds poorly to medical interventions, and is characterized by chronic vessel immaturity leading to lower extremity amputations.Objective: To define the role of reversible palmitoylation at the endothelium in the maintenance of vascular maturity.Methods and Results: Endothelial knockout of the depalmitoylation enzyme

  • In Situ Expansion, Differentiation and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered Organoid
    Circ. Res. (IF 15.862) Pub Date : 2020-03-31
    Molly E Kupfer; Wei-Han Lin; Vasanth Ravikumar; Kaiyan Qiu; Lu Wang; Ling Gao; Didarul Bhuiyan; Megan Lenz; Jeffrey Ai; Ryan R Mahutga; DeWayne Townsend; Jianyi Zhang; Michael C McAlpine; Elena G Tolkacheva; Brenda M Ogle

    Rationale: One goal of cardiac tissue engineering is the generation of a living, human pump in vitro that could replace animal models and eventually serve as an in vivo therapeutic. Models that replicate the geometrically complex structure of the heart, harboring chambers and large vessels with soft biomaterials, can be achieved using 3D bioprinting. Yet, inclusion of contiguous, living muscle to support

  • Epigenetic Metabolic Reprogramming of Right Ventricular Fibroblasts in Pulmonary Arterial Hypertension: A Pyruvate Dehydrogenase Kinase-Dependent Shift in Mitochondrial Metabolism Promotes Right Ventricular Fibrosis
    Circ. Res. (IF 15.862) Pub Date : 2020-03-27
    Lian Tian; Danchen Wu; Asish Dasgupta; Kuang-Hueih Chen; Jeffrey Mewburn; Francois Potus; Patricia AD Lima; Zhigang Hong; Yuan-Yuan Zhao; Charles Hindmarch; Shelby Kutty; Steeve Provencher; Sébastien Bonnet; Gopinath Sutendra; Stephen L Archer

    Rationale: Right ventricular (RV) fibrosis in pulmonary arterial hypertension (PAH) contributes to RV failure (RVF). While RV fibrosis reflects changes in the function of resident RV fibroblasts (RVfib), these cells are understudied.Objective: Examine the role of mitochondrial metabolism of RVfib in RV fibrosis in human and experimental PAH.Methods and Results: Male Sprague-Dawley rats received monocrotaline

  • miR-128-3p Is a Novel Regulator of Vascular Smooth Muscle Cell Phenotypic Switch and Vascular Diseases
    Circ. Res. (IF 15.862) Pub Date : 2020-03-27
    Floriana M Farina; Ignacio Fernando Hall; Simone Serio; Stefania Maria Zani; Montserrat Climent; Nicolò Salvarani; Pierluigi Carullo; Efrem Civilini; Gianluigi Condorelli; Leonardo Elia; Manuela Quintavalle

    Rationale: microRNAs (miRNAs) are small non-coding RNAs that modulate gene expression by negatively regulating translation of target genes. While the role of several miRNAs in vascular smooth muscle cells (VSMCs) has been extensively characterized, the function of miR-128-3p (miR-128) is still unknown.Objective: To determine if miR-128 modulates VSMC phenotype, and to define the underlying mechanisms

  • A Critical Role for Estrogen-Related Receptor Signaling in Cardiac Maturation
    Circ. Res. (IF 15.862) Pub Date : 2020-03-26
    Tomoya Sakamoto; Timothy R Matsuura; Shibiao Wan; David M Ryba; Junil Kim; Kyoung-Jae Won; Ling Lai; Christopher Petucci; Nataliya Petrenko; Kiran Musunuru; Rick B Vega; Daniel P Kelly

    Rationale: The heart undergoes dramatic developmental changes during the prenatal to postnatal transition, including maturation of cardiac myocyte energy metabolic and contractile machinery. Delineation of the mechanisms involved in cardiac postnatal development could provide new insight into the "fetal" shifts that occur in the diseased heart and unveil strategies for driving maturation of stem cell-derived

  • Cold-Inducible RNA-Binding Protein Prevents an Excessive Heart Rate Response to Stress by Targeting Phosphodiesterase
    Circ. Res. (IF 15.862) Pub Date : 2020-03-26
    Duanyang Xie; Li Geng; Ke Xiong; Tingting Zhao; Shuo Wang; Jinfeng Xue; Cheng Wang; Guanghua Wang; Zhiqiang Feng; Huixing Zhou; Yini Li; Li Li; Yi Liu; Zhigang Xue; Jian Yang; Honghui Ma; Dandan Liang; Yi-Han Chen

    Rationale: The stress response of heart rate (HR), which is determined by the plasticity of the sinus node (SAN), is essential for cardiac function and survival in mammals. As an RNA binding protein, cold-inducible RNA-binding protein (CIRP) can act as a stress regulator. Previously, we've documented that CIRP regulates cardiac electrophysiology at post-transcriptional level, suggesting its role in

  • In This Issue
    Circ. Res. (IF 15.862) Pub Date : 2020-03-26
    Ruth Williams

    In normal healthy hearts, the aorta and pulmonary arteries arise from the left and right ventricles, respectively. But in transposition of the great arteries (TGA), a common developmental heart malformation, the plumbing of these two major vessels is switched. The genetic etiology of this life-threatening condition, which requires surgery in the early days of life, is largely unknown. Liu and colleagues

  • Exome-Based Case-Control Analysis Highlights the Pathogenic Role of Ciliary Genes in Transposition of the Great Arteries.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-11
    Xuanyu Liu,Wen Chen,Wenke Li,James R Priest,Yuanyuan Fu,Kun-Jing Pang,Baihui Ma,Bianmei Han,Xuewen Liu,Shengshou Hu,Zhou Zhou

    Rationale: Transposition of the great arteries (TGA) is one of the most severe types of congenital heart diseases (CHD). Understanding the clinical characteristics and pathogenesis of TGA is therefore urgently needed for patient management of this severe disease. However, the clinical characteristics and genetic etiology underlying TGA remain largely unexplored. Objective: We sought to systematically

  • Mildly Abnormal Lipid Levels, but Not High Lipid Variability, Are Associated with Increased Risk of Myocardial Infarction and Stroke in 'Statin-Naive' Young Population: A Nationwide Cohort Study.
    Circ. Res. (IF 15.862) Pub Date : 2020-01-24
    Jun-Bean Park,Dahye Kim,Heesun Lee,In-Chang Hwang,Yeonyee Elizabeth Yoon,Hyo Eun Park,Su-Yeon Choi,Yong-Jin Kim,Goo-Yeong Cho,Kyung-Do Han,Hyung-Kwan Kim

    Rationale: In young adults, the role of mildly abnormal lipid levels and lipid variability in the risk of atherosclerotic cardiovascular diseases (ASCVDs) remains uncertain. Objective: To investigate the association of these abnormalities in lipid profiles with the risk of myocardial infarction (MI) and stroke in young population. Methods and Results: From the Korean National Health Insurance Service

  • Intestinal Flora Modulates Blood Pressure by Regulating the Synthesis of Intestinal-Derived Corticosterone in High Salt-Induced Hypertension.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-13
    Xuefang Yan,Jiajia Jin,Xinhuan Su,Xianlun Yin,Jing Gao,Xiaowei Wang,Shucui Zhang,Peili Bu,Mansen Wang,Yun Zhang,Zhe Wang,Qunye Zhang

    Rationale: High-salt diet (HSD) is one of the most important risk factors for hypertension. Intestinal flora has been reported to be associated with high salt-induced hypertension (hSIH). However, the detailed roles of intestinal flora in hSIH pathogenesis have not yet been fully elucidated. Objective: To reveal the roles and mechanisms of intestinal flora in hSIH development. Methods and Results:

  • N-Cadherin Overexpression Mobilizes the Protective Effects of Mesenchymal Stromal Cells Against Ischemic Heart Injury Through A Β-Catenin Dependent Manner.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-21
    Wenjun Yan,Chen Lin,Yongzhen Guo,Youhu Chen,Yunhui Du,Wayne Bond Lau,Yunlong Xia,Fuyang Zhang,Renzhi Su,Erhe Gao,Yajing Wang,Congye Li,Rui Liu,Xin-Liang Ma,Ling Tao

    Rationale: Mesenchymal stromal cells (MSC)-based therapy is promising against ischemic heart failure (IHF). However, its efficacy is limited due to low cell retention and poor paracrine function. A transmembrane protein capable of enhancing cell-cell adhesion, N-cadherin garnered attention in the field of stem cell biology only recently. Objective: The current study investigates whether and how N-cadherin

  • Genomic Characterization of Endothelial Enhancers Reveals a Multifunctional Role for NR2F2 in Regulation of Arteriovenous Gene Expression.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-17
    Samir Sissaoui,Jun Yu,Aimin Yan,Rui Li,Lihua J Zhu,Alper Kucukural,Onur Yukselen,Nathan D Lawson

    Rationale: Significant progress has revealed transcriptional inputs that underlie regulation of artery and vein endothelial cell fates. However, little is known concerning genome-wide regulation of this process. Therefore, such studies are warranted to address this gap. Objective: To identify and characterize artery- and vein-specific endothelial enhancers in the human genome, thereby gaining insights

  • Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-19
    Kiarash Tazmini,Michael Frisk,Alexandre Lewalle,Martin Laasmaa,Stefano Morotti,David B Lipsett,Ornella Manfra,Jonas Skogestad,Jan M Aronsen,Ole M Sejersted,Ivar Sjaastad,Andrew G Edwards,Eleonora Grandi,Steven Alexander Niederer,Erik Oie,William E Louch

    Rationale: Hypokalemia occurs in up to 20% of hospitalized patients, and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes. Objective: To investigate pro-arrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes. Methods

  • Ube2v1 Positively Regulates Protein Aggregation by Modulating Ubiquitin Proteasome System Performance Partially through K63 Ubiquitination.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-21
    Na Xu,James Gulick,Hanna Osinska,Yang Yu,Patrick M McLendon,Kritton Shay-Winkler,Jeffrey Robbins,Katherine E Yutzey

    Rationale: Compromised protein quality control can result in proteotoxic intracellular protein aggregates in the heart, leading to cardiac disease and heart failure. Defining the participants and understanding the underlying mechanisms of cardiac protein aggregation is critical for seeking therapeutic targets. We identified ubiquitin-conjugating enzyme E2 variant 1 (Ube2v1) in a genome-wide screen

  • Mitochondrial Determinants of Doxorubicin-Induced Cardiomyopathy
    Circ. Res. (IF 15.862) Pub Date : 2020-03-26
    Kendall B. Wallace; Vilma A. Sardão; Paulo J. Oliveira

    Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin is one of the most highly prescribed anthracyclines in the United States due to its broad spectrum of therapeutic efficacy. Interference with different mitochondrial processes is chief among the molecular and cellular determinants of doxorubicin cardiotoxicity, contributing

  • Targeting Myeloid-Specific Integrin α9β1 Improves Short and Long-Term Stroke Outcomes in Murine Models With Preexisting Comorbidities by Limiting Thrombosis And Inflammation
    Circ. Res. (IF 15.862) Pub Date : 2020-03-20
    Nirav Dhanesha; Manish Jain; Amit Tripathi; Prakash Doddapattar; Mehulkumar Chorawala; Girish Bathla; Manasa K Nayak; Madankumar Ghatge; Steven R Lentz; Shigeyuki Kon; Anil K Chauhan

    Rationale: Currently, there is no effective intervention available that can reduce brain damage following reperfusion. Clinical studies suggest a positive correlation between the increased influx of neutrophils and severity of brain injury following reperfusion. Integrin α9β1 is highly expressed on activated neutrophils and contributes to stable adhesion, but its role in stroke outcome has not been

  • The Noonan Syndrome Gene Lztr1 Controls Cardiovascular Function by Regulating Vesicular Trafficking
    Circ. Res. (IF 15.862) Pub Date : 2020-03-16
    Raj Nayan Sewduth; Silvia Pandolfi; Mikhail Steklov; Aidana Sheryazdanova; Peihua Zhao; Nathan Criem; Maria Francesca Baietti; Benoit Lechat; Rozenn Quarck; Francis Impens; Anna Sablina

    Rationale: Noonan syndrome (NS) is one of the most frequent genetic disorders. Bleeding problems are among the most common, yet poorly defined complications associated with NS. A lack of consensus on the management of bleeding complications in NS patients indicates an urgent need for new therapeutic approaches.Objective: Bleeding disorders have recently been described in NS patients harboring mutations

  • Reactivation of the Epicardium at the Origin of Myocardial Fibro-Fatty Infiltration During the Atrial Cardiomyopathy
    Circ. Res. (IF 15.862) Pub Date : 2020-03-16
    Nadine Suffee; Thomas Moore-Morris; Bernd Jagla; Nathalie Mougenot; Gilles Dilanian; Myriam Berthet; Julie Proukhnitzky; Pascal Leprince; David A Trégouët; Michel Puceat; Stephane N Hatem

    Rationale: Fibro-fatty infiltration of sub-epicardial layers of the atrial wall has been shown to contribute to the substrate of atrial fibrillation (AF).Objective: Here, we examined if the epicardium that contains multipotent cells is involved in this remodeling process.Methods and Results: 109 human surgical right atrial specimens were evaluated. There was a relatively greater extent of epicardial

  • In This Issue
    Circ. Res. (IF 15.862) Pub Date : 2020-03-12
    Ruth Williams

    Evidence suggests that T cells are involved in hypertension. Indeed, many stimuli that induce hypertension, including angiotensin II, high salt, and stress, also activate T cells. Once the stimulus abates, most of these cells will die, but a small number may go on to form memory T cells, which reside long-term in bone marrow and can be reactivated if the stimulus returns. Because hypertension increases

  • Meet the First Author
    Circ. Res. (IF 15.862) Pub Date : 2020-03-12

    Dr Oliver Rider earned his BA (1998), MD (2002), and PhD (2008) from Oxford University. His PhD in metabolic imaging was supervised by Dr Neubauer at the University of Oxford Centre for Clinical Magnetic Resonance Research (OCMR), and he was awarded an AHA Young Investigator Award in 2008. He became a Clinical Lecturer in 2010 and then Consultant Cardiologist and Deputy Clinical Director of OCMR in

  • 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

  • Non-Invasive In Vivo Assessment of Cardiac Metabolism in the Healthy and Diabetic Human Heart Using Hyperpolarized 13C MRI.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-05
    Oliver J Rider,Andrew Apps,Jack J Miller,Justin Yc Lau,Andrew Jm Lewis,Mark A Peterzan,Michael S Dodd,Angus Z Lau,Claire Trumper,Ferdia Gallagher,James T Grist,Kevin Brindle,Stefan Neubauer,Damian J Tyler

    Rationale: The recent development of hyperpolarized 13C Magnetic Resonance Spectroscopy (MRS) has made it possible to measure cellular metabolism in vivo, in real time. Objective: By comparing participants with and without type 2 diabetes (T2DM), we report the first case-control study to use this technique to record changes in cardiac metabolism in the healthy and diseased human heart. Methods and

  • A Novel "Cut And Paste" Method for In Situ Replacement of cMyBP-C Reveals a New Role for cMyBP-C in the Regulation of Contractile Oscillations.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-13
    Nathaniel Conrad Napierski,Kevin Granger,Paul R Langlais,Hannah R Moran,Joshua Strom,Katia D Youssef,Samantha P Harris

    Rationale: Cardiac myosin binding protein-C (cMyBP-C) is a critical regulator of heart contraction, but the mechanisms by which cMyBP-C affects actin and myosin are only partly understood. A primary obstacle is that cMyBP-C localization on thick filaments may be a key factor defining its interactions, but most in vitro studies cannot duplicate the unique spatial arrangement of cMyBP-C within the sarcomere

  • Brain Damage with Heart Failure: Cardiac Biomarker Alterations and Gray Matter Decline.
    Circ. Res. (IF 15.862) Pub Date : 2020-01-23
    Karsten Mueller,Friederike Thiel,Frank Beutner,Andrej Teren,Stefan Frisch,Tommaso Ballarini,Harald E Möller,Kristin Ihle,Joachim Thiery,Gerhard C Schuler,Arno Villringer,Matthias L Schroeter

    Rationale: Heart failure (HF) following heart damage leads to a decreased blood flow due to a reduced pump efficiency of the heart muscle. A consequence can be insufficient oxygen supply to the organism including the brain. While HF clearly shows neurological symptoms, such as fatigue, nausea and dizziness, the implications for brain structure are not well understood. Few studies show regional gray

  • BMAL1-Downregulation Aggravates Porphyromonas Gingivalis-Induced Atherosclerosis by Encouraging Oxidative Stress.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-11
    Mengru Xie,Qingming Tang,Jiaming Nie,Chao Zhang,Xin Zhou,Shaoling Yu,Jiwei Sun,Xiang Cheng,Nianguo Dong,Yu Hu,Lili Chen

    Rationale: Atherosclerotic cardiovascular diseases (ACVDs) are the leading cause of mortality worldwide. ACVDs are considered as chronic inflammation processes. In addition to risk factors associated with the cardiovascular system itself, pathogenic bacteria such as the periodontitis-associated Porphyromonas gingivalis (P. gingivalis) are also closely correlated with the development of atherosclerosis

  • Dll4 Suppresses Transcytosis for Arterial Blood-Retinal Barrier Homeostasis.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-12
    Jee Myung Yang,Chan Soon Park,Soo Hyun Kim,Tae Wook Noh,Ju-Hee Kim,Seongyeol Park,Jingu Lee,Jang Ryul Park,Dohyun Yoo,Hyun Ho Jung,Hiroshi Takase,David T Shima,Markus Schwaninger,Seungjoo Lee,Il-Kug Kim,Junyeop Lee,Yong-Sok Ji,Sangyong Jon,Wang-Yuhl Oh,Pilhan Kim,Akiyoshi Uemura,Young Seok Ju,Injune Kim

    Rationale: Central nervous system (CNS) has low vascular permeability by organizing tight junction (TJ) and limiting endothelial transcytosis. While TJ has long been considered to be responsible for barrier in CNS vessels, suppressed transcytosis in endothelial cells (ECs) is now emerging as a complementary mechanism. Whether transcytosis regulation is independent of TJ and its dysregulation dominantly

  • Obesity, Hypertension, and Cardiac Dysfunction
    Circ. Res. (IF 15.862) Pub Date : 2020-03-12
    Alan J. Mouton; Xuan Li; Michael E. Hall; John E. Hall

    Obesity and hypertension, which often coexist, are major risk factors for heart failure and are characterized by chronic, low-grade inflammation, which promotes adverse cardiac remodeling. While macrophages play a key role in cardiac remodeling, dysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypes promotes excessive inflammation and cardiac injury

  • Correction to: Lower Blood Pressure Thresholds Raise the Bar in Pregnancy
    Circ. Res. (IF 15.862) Pub Date : 2020-03-12

    In the article by Sinkey and Oparil, “Lower Blood Pressure Thresholds Raise the Bar in Pregnancy,” which published in the July 5, 2019 issue of the journal (Circ Res. 2019;125:195-197. doi: 10.1161/CIRCRESAHA.119.315384), a correction was needed. In the editorial,1 the authors state that Hu et al2 found gestational hypertension defined by the 2017 ACC/AHA Guideline “was significantly associated with

  • Atherogenic Lipoprotein(A) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation
    Circ. Res. (IF 15.862) Pub Date : 2020-03-12
    Jan Schnitzler; Renate Melanie Hoogeveen; Lubna Ali; Koen HM Prange; Farahnaz Waissi; Michel van Van Weeghel; Julian Christopher Bachmann; Miranda Versloot; Matthew J Borrelli; Calvin Yeang; Dominique de Kleijn; Riekelt H Houtkooper; Marlys Koschinsky; Menno PJ de Winther; Albert K Groen; Joseph L Witztum; Sotirios Tsimikas; Erik SG Stroes; Jeffrey Kroon

    Rationale: Patients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a pro-inflammatory state.Objective: We hypothesized that Lp(a) induces endothelial cell (EC) inflammation by rewiring endothelial metabolism.Methods and Results: We evaluated the impact of Lp(a) on the

  • PTH/PTHrP Receptor Signaling Restricts Arterial Fibrosis in Diabetic LDLR-/- Mice by Inhibiting Myocardin-Related Transcription Factor Relays
    Circ. Res. (IF 15.862) Pub Date : 2020-03-11
    Abraham Behrmann; Dalian Zhong; Li Li; Su-Li Cheng; Megan Mead; Bindu Ramachandran; Parastoo Sabaeifard; Mohammad Goodarzi; Andrew Lemoff; Henry M Kronenberg; Dwight A Towler

    Rationale: The PTH/PTHrP receptor (PTH1R) is expressed in vascular smooth muscle (VSM), and increased VSM PTH1R signaling mitigates diet-induced arteriosclerosis in LDLR-/- mice.Objective: To study the impact of VSM PTH1R deficiency, we generated mice SM22-Cre:PTH1R(fl/fl);LDLR-/- mice (PTH1R-VKO) and Cre-negative controls (CON).Methods and Results: Immunofluorescence and western blot confirmed PTH1R

  • Deep Phenotyping by Mass Cytometry and Single Cell RNA-Sequencing Reveals LYN Regulated Signaling Profiles Underlying Monocyte Subset Heterogeneity and Lifespan
    Circ. Res. (IF 15.862) Pub Date : 2020-03-10
    Morgan E Roberts; Maunish Barvalia; Jessica AFD Silva; Rachel A Cederberg; William Chu; Amanda Wong; Daven Tai; Sam Chen; Israel Matos; John Priatel; Pieter R cullis; Kenneth Harder

    Rationale: Monocytes are key effectors of the mononuclear phagocyte system (MPS), playing critical roles in regulating tissue homeostasis and coordinating inflammatory reactions, including those involved in chronic inflammatory diseases such as atherosclerosis. Monocytes have traditionally been divided into two major subsets termed conventional (cMo) and patrolling (pMo) monocytes but recent systems

  • AAV Gene Therapy Prevents and Reverses Heart Failure in A Murine Knockout Model of Barth Syndrome
    Circ. Res. (IF 15.862) Pub Date : 2020-03-09
    Suya Wang; Yifei Li; Yang Xu; Qing Ma; Zhiqiang Lin; Michael Schlame; Vassilios J. Bezzerides; Douglas Strathdee; William T. Pu

    Rationale: Barth syndrome (BTHS) is an X-linked cardiac and skeletal myopathy caused by mutation of the gene Tafazzin (TAZ). Currently there is no targeted treatment for BTHS. Lack of a proper genetic animal model that recapitulates the features of BTHS has hindered understanding of disease pathogenesis and therapeutic development.Objective: We characterized murine germline (TAZ-KO) and cardiac specific

  • EHD1 Modulates Cx43 Gap Junction Remodeling Associated with Cardiac Diseases
    Circ. Res. (IF 15.862) Pub Date : 2020-03-05
    Tania Martins-Marques; Steve Catarino; Alexandre Gonçalves; Daniela Miranda-Silva; Lino M Gonçalves; Pedro E Antunes; Gonçalo Coutinho; Adelino Leite-Moreira; Inês Falcão-Pires; Henrique Girao

    Rationale: Efficient communication between heart cells is vital to ensure the anisotropic propagation of electrical impulses, a function mainly accomplished by gap junctions (GJ) composed of Connexin43 (Cx43). Although the molecular mechanisms remain unclear, altered distribution and function of GJ have been associated with acute myocardial infarction and heart failure (HF).Objective: A recent proteomic

  • Endothelium-Targeted Deletion of microRNA-15a/16-1 Promotes Post-Stroke Angiogenesis and Improves Long-Term Neurological Recovery
    Circ. Res. (IF 15.862) Pub Date : 2020-03-05
    Ping Sun; Kai Zhang; Sulaiman H Hassan; Xuejing Zhang; Xuelian Tang; Hongjian Pu; R Anne Stetler; Jun Chen; Kejie Yin

    Rationale: Angiogenesis promotes neurological recovery after stroke and is associated with longer survival of stroke patients. Cerebral angiogenesis is tightly controlled by certain microRNAs (miRs), such as the miR-15a/16-1 cluster, among others. However, the function of the miR-15a/16-1 cluster in endothelium on post-ischemic cerebral angiogenesis is not known.Objective: To investigate the functional

  • Hyperglycemia Acutely Increases Cytosolic Reactive Oxygen Species via O-linked GlcNAcylation and CaMKII Activation in Mouse Ventricular Myocytes
    Circ. Res. (IF 15.862) Pub Date : 2020-03-05
    Shan Lu; Zhandi Liao; Xiyuan Lu; Dörthe M Katschinski; Mark Mercola; Ju Chen; Joan Heller Brown; Jeffery D. Molkentin; Julie Bossuyt; Donald M Bers

    Rationale: Diabetes mellitus (DM) is a complex, multisystem disease, affecting large populations worldwide. Chronic CaMKII activation may occur in DM and be arrhythmogenic. Diabetic hyperglycemia was shown to activate CaMKII by (1) O-linked attachment of N-acetylglucosamine (O-GlcNAc) at S280 leading to arrhythmia and (2) a reactive-oxygen species (ROS) mediated oxidation of CaMKII, that can increase

  • Targeting Treatment Refractory NET by EZH2 Inhibition in Postural Tachycardia Syndrome.
    Circ. Res. (IF 15.862) Pub Date : 2020-03-03
    Harikrishnan Kaipananickal,Abdul Waheed Khan,Susan J Corcoran,Murray D Esler,Jun Okabe,Assam El-Osta

  • In This Issue.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-27
    Ruth Williams

    In peripheral artery disease (PAD), blood flow to the limbs is limited as a result of vessel narrowing from atherosclerotic plaque build up. The symptoms are particularly noticeable in the legs making walking painful and, as the disease progresses, increasingly limited. Interventions that improve blood flow may alleviate the pain and increase mobility. To that end, McDermott and colleagues investigated

  • 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 H Lindeman,Fabrizio Veglia,Steve E Humphries,Ulf de Faire,Damiano Baldassarre,Elena Tremoli,,Janne Lehtiö,Göran K Hansson,Gabrielle Paulsson-Berne,Gerard Pasterkamp

    RATIONALE PCSKs (Proprotein convertase subtilisins/kexins) 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 remodeling, and mitogens. OBJECTIVE Here, we applied a systems biology approach to gain deeper insights into the PCSK6 role

  • Cocoa to Improve Walking Performance in Older People With Peripheral Artery Disease: The COCOA-PAD Pilot Randomized Clinical Trial.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-14
    Mary M McDermott,Michael H Criqui,Kathryn Domanchuk,Luigi Ferrucci,Jack M Guralnik,Melina R Kibbe,Kate Kosmac,Christopher M Kramer,Christiaan Leeuwenburgh,Lingyu Li,Donald Lloyd-Jones,Charlotte A Peterson,Tamar S Polonsky,James H Stein,Robert Sufit,Linda Van Horn,Francisco Villarreal,Dongxue Zhang,Lihui Zhao,Lu Tian

    RATIONALE Cocoa and its major flavanol component, epicatechin, have therapeutic properties that may improve limb perfusion and increase calf muscle mitochondrial activity in people with lower extremity peripheral artery disease (PAD). OBJECTIVE In a phase II randomized clinical trial, to assess whether 6 months of cocoa improved walking performance in people with PAD, compared with placebo. METHODS

  • Eating Chocolate to Improve Muscle Health and Walking Ability in Patients With Peripheral Artery Disease.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-14
    Reiko Matsui,Naomi M Hamburg

    Peripheral artery disease (PAD) is rising in worldwide along with population aging. Patients with PAD experience chronic leg ischemia that impairs walking ability. Obstruction to distal blood flow to leg muscle due to atherosclerotic lesions characterizes peripheral artery disease. However, a simple model of reduced blood supply due to arterial stenosis does not fully explain functional limitations

  • Enhanced CaMKII-Dependent Late INa Induces Atrial Proarrhythmic Activity in Patients With Sleep-Disordered Breathing.
    Circ. Res. (IF 15.862) Pub Date : 2020-01-06
    Simon Lebek,Konstantin Pichler,Kathrin Reuthner,Maximillian Trum,Maria Tafelmeier,Julian Mustroph,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 CaMKII (Ca/calmodulin-dependent protein kinase II) activity has been previously implicated in atrial arrhythmogenesis. OBJECTIVE We hypothesized that CaMKII-dependent dysregulation of Na current (INa) may contribute to atrial proarrhythmic activity in patients with SDB. METHODS AND RESULTS We prospectively

  • 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 M Almonte,Jingy Chi,Tao Tong,Gustavo H Oliveira-Paula,Issam Koleilat,Wei Chen,Paul Cohen,Nicholas E S 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

  • Life-Course Cumulative Burden of Body Mass Index and Blood Pressure on Progression of Left Ventricular Mass and Geometry in Midlife: The Bogalusa Heart Study.
    Circ. Res. (IF 15.862) Pub Date : 2020-01-29
    Yinkun Yan,Shengxu Li,Yajun Guo,Camilo Fernandez,Lydia Bazzano,Jiang He,Jie Mi,Wei Chen,

    RATIONALE Data are limited regarding the influence of life-course cumulative burden of increased body mass index (BMI) and elevated blood pressure (BP) on the progression of left ventricular (LV) geometric remodeling in midlife. OBJECTIVE To investigate the dynamic changes in LV mass and LV geometry over 6.4 years during midlife and to examine whether the adverse progression of LV geometric remodeling

  • Identification of a Primary Renal AT2 Receptor Defect in Spontaneously Hypertensive Rats.
    Circ. Res. (IF 15.862) Pub Date : 2020-01-30
    Brandon A Kemp,Nancy L Howell,John J Gildea,Susanna R Keller,Robert M Carey

    RATIONALE Previous studies identified a defect in Ang III (angiotensin III [des-aspartyl1-angiotensin II])-elicited AT2R (Ang type-2 receptor)-mediated natriuresis in renal proximal tubule cells of spontaneously hypertensive rats (SHR). OBJECTIVE This study aimed to delineate in prehypertensive SHR kidneys the receptor or postreceptor defect causing impaired AT2R signaling and renal sodium (Na+) retention

  • Preclinical and Clinical Development of Noncoding RNA Therapeutics for Cardiovascular Disease.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-27
    Cheng-Kai Huang,Sabine Kafert-Kasting,Thomas Thum

    RNA modulation has become a promising therapeutic approach for the treatment of several types of disease. The emerging field of noncoding RNA-based therapies has now come to the attention of cardiovascular research, in which it could provide valuable advancements in comparison to current pharmacotherapy such as small molecule drugs or antibodies. In this review, we focus on noncoding RNA-based studies

  • Nonalcoholic Fatty Liver Disease Pandemic Fuels the Upsurge in Cardiovascular Diseases.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-27
    Jingjing Cai,Xiao-Jing Zhang,Yan-Xiao Ji,Peng Zhang,Zhi-Gang She,Hongliang Li

    Cardiovascular diseases (CVDs) remain a leading cause of death worldwide. Among the major risk factors for CVD, obesity and diabetes mellitus have received considerable attention in terms of public policy and awareness. However, the emerging prevalence of nonalcoholic fatty liver disease (NAFLD), as the most common liver and metabolic disease and a cause of CVD, has been largely overlooked. Currently

  • 更新日期:2020-02-27
  • PCSK6-Mediated Regulation of Vascular Remodeling.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-27
    Helle F Jørgensen,Martin R Bennett

  • Meet the First Author.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-27

  • 更新日期:2020-02-27
  • Celastrol Attenuates Angiotensin II-Induced Cardiac Remodeling by Targeting STAT3.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-26
    Shiju Ye,Wu Luo,Zia A Khan,Gaojun Wu,Lina Xuan,Peiren Shan,Ke Lin,Taiwei Chen,Jingying Wang,Xiang Hu,Shengjie Wang,Weijian Huang,Guang Liang

    Rationale: Excessive angiotensin II (Ang II) levels lead to a pro-fibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II-induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure. Objective: We have examined the potential effect of Celastrol, a bioactive

  • Crystal Clots as Therapeutic Target in Cholesterol Crystal Embolism.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-24
    Chongxu Shi,Tehyung Kim,Stefanie Steiger,Shrikant Ramesh Mulay,Barbara Mara Klinkhammer,Tobias Bäuerle,Maria Elena Melica,Paola Romagnani,Diana Möckel,Maike Baues,Elmina Mammadova-Bach,Luying Yang,Sanne Ln Brouns,Johan Wm Heemskerk,Attila Braun,Twan Lammers,Peter Boor,Hans-Joachim Anders

    Rationale: Cholesterol crystal embolism (CCE) can be a life-threatening complication of advanced atherosclerosis. Pathophysiology and molecular targets for treatment are largely unknown. Objective: We aimed to develop a new animal model of CCE to dissect the molecular mechanisms of cholesterol crystal (CC)-driven arterial occlusion, tissue infarction, and organ failure.Methods and Results: C57BL/6J

  • A Computational Pipeline to Predict Cardiotoxicity:From the Atom to the Rhythm.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-24
    Pei-Chi Yang,Kevin R DeMarco,Parya Aghasafari,Mao-Tsuen Jeng,John Rd Dawson,Slava Bekker,Sergei Noskov,Vladimir Yarov-Yarovoy,Igor Vorobyov,Colleen E Clancy

    Rationale: Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery. Objective: To predict the impact of a drug from the drug chemistry on the cardiac rhythm. Methods and Results:

  • Nfatc1 Promotes Interstitial Cell Formation During Cardiac Valve Development in Zebrafish.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-18
    Felix Gunawan,Alessandra Gentile,Sebastien Gauvrit,Didier Stainier,Anabela Bensimon-Brito

    Rationale: The transcription factor NFATC1 has been implicated in cardiac valve formation in humans and mice, but we know little about the underlying mechanisms. To gain mechanistic understanding of cardiac valve formation at single cell resolution and insights into the role of NFATC1 in this process, we used the zebrafish model as it offers unique attributes for live imaging and facile genetics. Objective:

  • RNA Sequencing Analysis of Induced Pluripotent Stem Cell-Derived Cardiomyocytes from Congenital Heart Disease Patients.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-19
    Tomoya Kitani,Lei Tian,Tiejun Zhang,Ilanit Itzhaki,Joe Z Zhang,Ning Ma,Chun Liu,June-Wha Rhee,Anitra Romfh,George K Lui,Joseph C Wu

  • T Cell-Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension.
    Circ. Res. (IF 15.862) Pub Date : 2020-02-17
    Ryszard Nosalski,Mateusz Siedlinski,Laura Denby,Eilidh McGinnigle,Michał Nowak,Aurelie Nguyen Dinh Cat,Laura Medina-Ruiz,Marco Cantini,Dominik Skiba,Grzegorz Wilk,Grzegorz Osmenda,Julie Rodor,Manuel Salmeron-Sanchez,Gerard Graham,Pasquale Maffia,Delyth Graham,Andrew H Baker,Tomasz J Guzik

    Rationale: Despite increasing understanding of the prognostic importance of vascular stiffening linked to perivascular fibrosis in hypertension, the molecular and cellular regulation of this process is poorly understood. Objective: To study the functional role of microRNA-214 (miR-214) in the induction of perivascular fibrosis and endothelial dysfunction driving vascular stiffening. Methods and Results:

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