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  • Trimethylamine-N-Oxide Promotes Vascular Calcification Through Activation of NLRP3 (Nucleotide-Binding Domain, Leucine-Rich-Containing Family, Pyrin Domain-Containing-3) Inflammasome and NF-κB (Nuclear Factor κB) Signals
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2020-01-16
    Xiuli Zhang; Yining Li; Pingzhen Yang; Xiaoyu Liu; Lihe Lu; Yanting Chen; Xinglong Zhong; Zehua Li; Hailin Liu; Caiwen Ou; Jianyun Yan; Minsheng Chen

    Objectives:Vascular calcification is highly prevalent in patients with chronic kidney disease. Increased plasma trimethylamine N-oxide (TMAO), a gut microbiota-dependent product, concentrations are found in patients undergoing hemodialysis. However, a clear mechanistic link between TMAO and vascular calcification is not yet established. In this study, we investigate whether TMAO participates in the progression of vascular calcification using in vitro, ex vivo, and in vivo models.Approach and Results:Alizarin red staining revealed that TMAO promoted calcium/phosphate-induced calcification of rat and human vascular smooth muscle cells in a dose-dependent manner, and this was confirmed by calcium content assay. Similarly, TMAO upregulated the expression of bone-related molecules including Runx2 (Runt-related transcription factor 2) and BMP2 (bone morphogenetic protein-2), suggesting that TMAO promoted osteogenic differentiation of vascular smooth muscle cells. In addition, ex vivo study also showed the positive regulatory effect of TMAO on vascular calcification. Furthermore, we found that TMAO accelerated vascular calcification in rats with chronic kidney disease, as indicated by Mico-computed tomography analysis, alizarin red staining and calcium content assay. By contrast, reducing TMAO levels by antibiotics attenuated vascular calcification in chronic kidney disease rats. Interestingly, TMAO activated NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome and NF-κB (nuclear factor κB) signals during vascular calcification. Inhibition of NLRP3 inflammasome and NF-κB signals attenuated TMAO-induced vascular smooth muscle cells calcification.Conclusions:This study for the first time demonstrates that TMAO promotes vascular calcification through activation of NLRP3 inflammasome and NF-κB signals, suggesting the potential link between gut microbial metabolism and vascular calcification. Reducing the levels of TMAO could become a potential treatment strategy for vascular calcification in chronic kidney disease.

    更新日期:2020-01-16
  • Homocysteine Level Predicts Response to Dual Antiplatelet in Women With Minor Stroke or Transient Ischemic Attack
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2020-01-16
    Jiejie Li; Yilong Wang; Hao Li; Zhiyi Zuo; Jinxi Lin; Anxin Wang; Xingquan Zhao; Liping Liu; Yongjun Wang; on behalf of the CHANCE Investigators*

    Objectives:To investigate the relationship of homocysteine levels with the efficacy and safety of dual antiplatelet therapy in female and male patients.Approach and Results:The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) randomized patients with acute minor ischemic stroke or high-risk transient ischemic attack to clopidogrel plus aspirin or aspirin alone from October 1, 2009, to July 30, 2012, in China. A subgroup of 3044 consecutive patients with baseline homocysteine levels from 73 (64%) prespecified clinical sites was analyzed. Participants were grouped by sex. Primary outcome was stroke recurrence within 90 days. Secondary outcomes consisted of composite vascular events and independent living or death. Safety outcome was any bleeding. Cox proportional-hazards models were used to assess the interaction of homocysteine levels with randomized antiplatelet therapy on efficacy and safety outcomes. A significant interaction between homocysteine levels and the randomized antiplatelet therapies was found on recurrent stroke after adjustment for confounding factors in women (P=0.010) but not in men (P=0.595). Compared with aspirin alone, clopidogrel plus aspirin significantly reduced the risk of recurrent stroke in women without elevated homocysteine levels (adjusted hazard ratio, 0.459 [95% CI, 0.271–0.776]; P=0.004). Such benefit disappeared in female patients with increased homocysteine level. No significant interaction on functional outcome or bleeding rate was observed.Conclusions:Homocysteine could be a potential biomarker to discriminate the effects of dual and single antiplatelet therapy in female patients with minor ischemic stroke or high-risk transient ischemic attack.Clinical Trial Registration:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589.

    更新日期:2020-01-16
  • High Brown Fat Activity Correlates With Cardiovascular Risk Factor Levels Cross-Sectionally and Subclinical Atherosclerosis at 5-Year Follow-Up
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2020-01-16
    Juho Raiko; Janne Orava; Nina Savisto; Kirsi A. Virtanen

    Objective:Brown adipose tissue (BAT) activity correlates negatively with obesity and insulin resistance, and BAT has been suggested to act as a protective factor against atherogenesis. We aimed to examine subclinical atherosclerosis and risk factor levels in a group of individuals who had 5 years earlier participated in positron-emission tomography studies with measurements of BAT activity.Approach and Results:Study cohort (M/F=5/26, baseline age 41.4±7.9 years; body mass index, 26.8±6.3 kg/m2) underwent positron-emission tomography imaging at baseline with [18F] FDG (glucose uptake) and [15O] H2O (perfusion) to measure BAT activity during cold exposure. At 5-year follow-up, ultrasound was performed to measure carotid intima-media thickness, carotid distensibility (a marker of arterial elasticity), and brachial flow-mediated dilation (an estimate of endothelial function). Fasting plasma lipids and HbA1c were measured from venous samples at baseline and at follow-up. Median values were used as cut points for high cold-induced BAT activity (BAT glucose uptake >2.40 μmoL/100 g per minute and perfusion >8.4 mL/100 g per minute). Baseline cold-induced BAT glucose uptake and perfusion correlated directly with carotid distensibility and inversely with mean bulbus intima-media thickness and maximum intima-media thickness (P always ≤0.02). Baseline body mass index, plasma triglycerides, and HbA1c correlated negatively with BAT glucose uptake and perfusion in cold (P always ≤0.048). Correlations between cold-induced BAT activity, cardiovascular risk factors, and atherosclerosis were attenuated with corrections for multiple comparisons.Conclusions:Cold-induced BAT activity at baseline seems to correlate with lower levels of conventional cardiovascular risk factors at baseline and with lower carotid intima-media thickness and higher carotid elasticity at 5-year follow-up.

    更新日期:2020-01-16
  • Disruption of PLTP (Phospholipid Transfer Protein)-Mediated HDL (High-Density Lipoprotein) Maturation Reduces SR-BI (Scavenger Receptor BI) Deficiency–Driven Atherosclerosis Susceptibility Despite Unexpected Metabolic Complications
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2020-01-16
    Menno Hoekstra; Ronald J. van der Sluis; Reeni B. Hildebrand; Bart Lammers; Ying Zhao; Domenico Praticò; Theo J.C. van Berkel; Patrick C.N. Rensen; Sander Kooijman; Matti Jauhiainen; Miranda van Eck

    Objective:We tested the hypothesis that enlarged, dysfunctional HDL (high-density lipoprotein) particles contribute to the augmented atherosclerosis susceptibility associated with SR-BI (scavenger receptor BI) deficiency in mice.Approach and Results:We eliminated the ability of HDL particles to fully mature by targeting PLTP (phospholipid transfer protein) functionality. Particle size of the HDL population was almost fully normalized in male and female SR-BI×PLTP double knockout mice. In contrast, the plasma unesterified cholesterol to cholesteryl ester ratio remained elevated. The PLTP deficiency-induced reduction in HDL size in SR-BI knockout mice resulted in a normalized aortic tissue oxidative stress status on Western-type diet. Atherosclerosis susceptibility was—however—only partially reversed in double knockout mice, which can likely be attributed to the fact that they developed a metabolic syndrome-like phenotype characterized by obesity, hypertriglyceridemia, and a reduced glucose tolerance. Mechanistic studies in chow diet–fed mice revealed that the diminished glucose tolerance was probably secondary to the exaggerated postprandial triglyceride response. The absence of PLTP did not affect LPL (lipoprotein lipase)-mediated triglyceride lipolysis but rather modified the ability of VLDL (very low-density lipoprotein)/chylomicron remnants to be cleared from the circulation by the liver through receptors other than SR-BI. As a result, livers of double knockout mice only cleared 26% of the fractional dose of [14C]cholesteryl oleate after intravenous VLDL-like particle injection.Conclusions:We have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in mice despite the induction of proatherogenic metabolic complications in the double knockout mice.

    更新日期:2020-01-16
  • Short-Term Exposure to Waterpipe/Hookah Smoke Triggers a Hyperactive Platelet Activation State and Increases the Risk of Thrombogenesis
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2020-01-16
    Ahmed B. Alarabi; Zubair A. Karim; Jean E. Montes Ramirez; Keziah R. Hernandez; Patricia A. Lozano; José O. Rivera; Fatima Z. Alshbool; Fadi T. Khasawneh

    Objective:Cardiovascular disease is a major public health problem. Among cardiovascular disease’s risk factors, tobacco smoking is considered the single most preventable cause of death, with thrombosis being the main mechanism of cardiovascular disease mortality in smokers. While tobacco smoking has been on the decline, the use of waterpipes/hookah has been rising, mainly due to the perception that they are less harmful than regular cigarettes. Strikingly, there are few studies on the negative effects of waterpipes on the cardiovascular system, and none regarding their direct contribution to thrombus formation.Approach and Results:We used a waterpipe whole-body exposure protocol that mimics real-life human exposure scenarios and investigated its effects, relative to clean air, on platelet function, hemostasis, and thrombogenesis. We found that waterpipe smoke (WPS)–exposed mice exhibited both shortened thrombus occlusion and bleeding times. Further, our results show that platelets from WPS-exposed mice are hyperactive, with enhanced agonist-induced aggregation, dense and α-granule secretion, αIIbβ3 integrin activation, phosphatidylserine expression, and platelet spreading, when compared with clean air–exposed platelets. Finally, at the molecular level, it was found that Akt (protein kinase B) and ERK (extracellular signal-regulated kinases) phosphorylation are enhanced in the WPS and in nicotine-treated platelets.Conclusions:Our findings demonstrate that WPS exposure directly modulates hemostasis and increases the risk of thrombosis and that this is mediated, in part, via a state of platelet hyperactivity. The negative health impact of WPS/hookah, therefore, should not be underestimated. Moreover, this study should also help in raising public awareness of the toxic effects of waterpipe/hookah.Visual Overview: An online visual overview is available for this article.

    更新日期:2020-01-16
  • Effects of Post-Translational Modifications of Fibrinogen on Clot Formation, Clot Structure, and Fibrinolysis
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2020-01-09
    Judith J. de Vries; Charlotte J.M. Snoek; Dingeman C. Rijken; Moniek P.M. de Maat

    Objective:Post-translational modifications of fibrinogen influence the occurrence and progression of thrombotic diseases. In this systematic review, we assessed the current literature on post-translational modifications of fibrinogen and their effects on fibrin formation and clot characteristics.Approach and Results:A systematic search of Medline, Embase, Cochrane Library, and Web of Science was performed to find studies reporting post-translational modifications of fibrinogen and the effects on clot formation and structure. Both in vitro studies and ex vivo studies using patient material were included. One hundred five articles were included, describing 11 different modifications of fibrinogen. For the best known and studied modifications, conclusions could be drawn about their effect on clot formation and structure. Oxidation, high levels of nitration, and glycosylation inhibit the rate of polymerization, resulting in dense clots with thinner fibers, while low levels of nitration increase the rate of polymerization. Glycation showed different results for polymerization, but fibrinolysis was found to be decreased, as a consequence of increased density and decreased permeability of clots. Acetylation also decreases the rate of polymerization but results in increased fiber diameters and susceptibility to fibrinolysis. Other modifications were studied less or contrasting results were found. Therefore, substantial gaps in the knowledge about the effect of post-translational modifications remain.Conclusions:Overall, post-translational modifications do affect clot formation and characteristics. More studies need to be performed to reveal the effects of all post-translational modifications and the effects on thrombotic diseases. Expanding the knowledge about modifications of fibrinogen can ultimately contribute to optimizing treatments for thrombotic diseases.

    更新日期:2020-01-09
  • Noncoding RNAs in Critical Limb Ischemia
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2020-01-02
    Daniel Pérez-Cremades; Henry S. Cheng; Mark W. Feinberg

    Peripheral artery disease, caused by chronic arterial occlusion of the lower extremities, affects over 200 million people worldwide. Peripheral artery disease can progress into critical limb ischemia (CLI), its more severe manifestation, which is associated with higher risk of limb amputation and cardiovascular death. Aiming to improve tissue perfusion, therapeutic angiogenesis held promise to improve ischemic limbs using delivery of growth factors but has not successfully translated into benefits for patients. Moreover, accumulating studies suggest that impaired downstream signaling of these growth factors (or angiogenic resistance) may significantly contribute to CLI, particularly under harsh environments, such as diabetes mellitus. Noncoding RNAs are essential regulators of gene expression that control a range of pathophysiologies relevant to CLI, including angiogenesis/arteriogenesis, hypoxia, inflammation, stem/progenitor cells, and diabetes mellitus. In this review, we summarize the role of noncoding RNAs, including microRNAs and long noncoding RNAs, as functional mediators or biomarkers in the pathophysiology of CLI. A better understanding of these ncRNAs in CLI may provide opportunities for new targets in the prevention, diagnosis, and therapeutic management of this disabling disease state.

    更新日期:2020-01-04
  • NFκB (Nuclear Factor κ-Light-Chain Enhancer of Activated B Cells) Activity Regulates Cell-Type–Specific and Context-Specific Susceptibility to Calcification in the Aortic Valve
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2020-01-02
    Terence Gee; Emily Farrar; Yidong Wang; Bingruo Wu; Kevin Hsu; Bin Zhou; Jonathan Butcher

    Objective:Although often studied independently, little is known about how aortic valve endothelial cells and valve interstitial cells interact collaborate to maintain tissue homeostasis or drive valve calcific pathogenesis. Inflammatory signaling is a recognized initiator of valve calcification, but the cell-type–specific downstream mechanisms have not been elucidated. In this study, we test how inflammatory signaling via NFκB (nuclear factor κ-light-chain enhancer of activated B cells) activity coordinates unique and shared mechanisms of valve endothelial cells and valve interstitial cells differentiation during calcific progression.Approach and Results:Activated NFκB was present throughout the calcific aortic valve disease (CAVD) process in both endothelial and interstitial cell populations in an established mouse model of hypercholesterolemia-induced CAVD and in human CAVD. NFκB activity induces endothelial to mesenchymal transformation in 3-dimensional cultured aortic valve endothelial cells and subsequent osteogenic calcification of transformed cells. Similarly, 3-dimensional cultured valve interstitial cells calcified via NFκB-mediated osteogenic differentiation. NFκB-mediated endothelial to mesenchymal transformation was directly demonstrated in vivo during CAVD via genetic lineage tracking. Genetic deletion of NFκB in either whole valves or valve endothelium only was sufficient to prevent valve-specific molecular and cellular mechanisms of CAVD in vivo despite the persistence of a CAVD inducing environment.Conclusions:Our results identify NFκB signaling as an essential molecular regulator for both valve endothelial and interstitial participation in CAVD pathogenesis. Direct demonstration of valve endothelial cell endothelial to mesenchymal transformation transmigration in vivo during CAVD highlights a new cellular population for further investigation in CAVD morbidity. The efficacy of valve-specific NFκB modulation in inhibiting hypercholesterolemic CAVD suggests potential benefits of multicell type integrated investigation for biological therapeutic development and evaluation for CAVD.

    更新日期:2020-01-04
  • Native, Intact Glucagon-Like Peptide-1 Is a Natural Suppressor of Thrombus Growth Under Physiological Flow Conditions
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2020-01-02
    Marieke Sternkopf; Magdolna Nagy; Constance C.F.M.J. Baaten; Marijke J.E. Kuijpers; Bibian M.E. Tullemans; Julia Wirth; Wendy Theelen; Tom G. Mastenbroek; Michael Lehrke; Benjamin Winnerling; Lesley Baerts; Nikolaus Marx; Ingrid De Meester; Yvonne Döring; Judith M.E.M. Cosemans; Andreas Daiber; Sebastian Steven; Joachim Jankowski; Johan W.M. Heemskerk; Heidi Noels

    Objective:In patients with diabetes mellitus, increased platelet reactivity predicts cardiac events. Limited evidence suggests that DPP-4 (dipeptidyl peptidase 4) influences platelets via GLP-1 (glucagon-like peptide 1)-dependent effects. Because DPP-4 inhibitors are frequently used in diabetes mellitus to improve the GLP-1-regulated glucose metabolism, we characterized the role of DPP-4 inhibition and of native intact versus DPP-4-cleaved GLP-1 on flow-dependent thrombus formation in mouse and human blood.Approach and Results:An ex vivo whole blood microfluidics model was applied to approach in vivo thrombosis and study collagen-dependent platelet adhesion, activation, and thrombus formation under shear-flow conditions by multiparameter analyses. In mice, in vivo inhibition or genetic deficiency of DPP-4 (Dpp4−/−), but not of GLP-1-receptors (Glp1r−/−), suppressed flow-dependent platelet aggregation. In human blood, GLP-1(7-36), but not DPP-4-cleaved GLP-1(9-36), reduced thrombus volume by 32% and impaired whole blood thrombus formation at both low/venous and high/arterial wall-shear rates. These effects were enforced on ADP costimulation and occurred independently of plasma factors and leukocytes. Human platelets did not contain detectable levels of GLP-1-receptor transcripts. Also, GLP-1(7-36) did not inhibit collagen-induced aggregation under conditions of stirring or stasis of platelets, pointing to a marked flow-dependent role.Conclusions:Native, intact GLP-1 is a natural suppressor of thrombus growth under physiological flow conditions, with DPP-4 inhibition and increased intact GLP-1 suppressing platelet aggregation under flow without a main relevance of GLP-1-receptor on platelets.

    更新日期:2020-01-04
  • Stabilization of Perivascular Mast Cells by Endothelial CNP (C-Type Natriuretic Peptide)
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2020-01-02
    Wen Chen; Franziska Werner; Anja Illerhaus; Tanja Knopp; Katharina Völker; Tamara Potapenko; Ulrich Hofmann; Stefan Frantz; Hideo A. Baba; Melanie Rösch; Alma Zernecke; Susanne Karbach; Philip Wenzel; Michaela Kuhn

    Objective:Activated perivascular mast cells (MCs) participate in different cardiovascular diseases. Many factors provoking MC degranulation have been described, while physiological counterregulators are barely known. Endothelial CNP (C-type natriuretic peptide) participates in the maintenance of vascular barrier integrity, but the target cells and mechanisms are unclear. Here, we studied whether MCs are regulated by CNP.Approach and Results:In cultured human and murine MCs, CNP activated its specific GC (guanylyl cyclase)-B receptor and cyclic GMP signaling. This enhanced cyclic GMP–dependent phosphorylation of the cytoskeleton-associated VASP (vasodilator-stimulated phosphoprotein) and inhibited ATP-evoked degranulation. To elucidate the relevance in vivo, mice with a floxed GC-B (Npr2) gene were interbred with a Mcpt5-CreTG line to generate mice lacking GC-B in connective tissue MCs (MC GC-B KO). In anesthetized mice, acute ischemia-reperfusion of the cremaster muscle microcirculation provoked extensive MC degranulation and macromolecule extravasation. Superfusion of CNP markedly prevented MC activation and endothelial barrier disruption in control but not in MC GC-B KO mice. Notably, already under resting conditions, such KO mice had increased numbers of degranulated MCs in different tissues, together with elevated plasma chymase levels. After transient coronary occlusion, their myocardial areas at risk and with infarction were enlarged. Moreover, MC GC-B KO mice showed augmented perivascular neutrophil infiltration and deep vein thrombosis in a model of inferior vena cava ligation.Conclusions:CNP, via GC-B/cyclic GMP signaling, stabilizes resident perivascular MCs at baseline and prevents their excessive activation under pathological conditions. Thereby CNP contributes to the maintenance of vascular integrity in physiology and disease.

    更新日期:2020-01-04
  • Prothrombin Arg541Trp Mutation Leads to Defective PC (Protein C) Pathway Activation and Constitutes a Novel Genetic Risk Factor for Venous Thrombosis
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-26
    Xi Wu; Jing Dai; Xiaoqian Xu; Fang Li; Lei Li; Yeling Lu; Qin Xu; Qiulan Ding; Wenman Wu; Xuefeng Wang

    Objective:Defective PC (protein C) pathway predisposes patients to venous thromboembolism (VTE) and is mostly, but not exclusively, attributed to hereditary PC or PS (protein S) deficiencies and activated PC resistance caused by factor V Leiden mutation.Approach and Results:In a patient with acute mesenteric venous thrombosis and positive family history of VTE associated with the impaired PC pathway function determined by thrombin generation test, we identified a novel heterozygous prothrombin mutation p.Arg541Trp. Two more patients with positive family history of VTE carrying the same mutation were identified in a cohort of another 373 unrelated patients, making an overall prevalence of 0.8%. Family investigation revealed 11 individuals in the 3 pedigrees harboring the heterozygous prothrombin p.Arg541Trp mutation, and 8 of them (72%) had experienced episodes of VTE. Functional studies indicated the mutation moderately decreased procoagulant activity of prothrombin and had mild impact on the inactivation of thrombin by its inhibitor antithrombin. However, the amino acid residue substitution significantly compromised PC activation by thrombin, both in the absence and presence of soluble thrombomodulin, and thus rendered prothrombin function procoagulant biased.Conclusions:In summary, the prothrombin p.Arg541Trp mutation constitutes a new genetic risk factor of VTE by impairing function of PC pathway and tilting thrombin’s procoagulant activity over anticoagulant function.

    更新日期:2019-12-27
  • 18F-NaF PET/CT in Ex Vivo Human Coronary Arteries With Histological Correlation
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-26
    Trisha Youn; Subhi J. Al’Aref; Navneet Narula; Steven Salvatore; David Pisapia; Marc R. Dweck; Jagat Narula; Fay Y. Lin; Yao Lu; Amit Kumar; Renu Virmani; James K. Min

    Objective:18F-NaF PET activity correlates with high-risk plaque. We examined the correlation between 18F-NaF PET activity and extent of calcification (microcalcification and macrocalcification) in coronary arteries.Approach and Results:Eighteen ex vivo human coronary arteries were imaged with 18F-NaF PET/CT, and target to background ratios were analyzed from 101 plaques. Histopathologic analysis evaluated for microcalcification and macrocalcification, plaque morphology, and inflammation. Plaques with microcalcification demonstrated higher 18F-NaF PET activity (n=84; mean target to background ratio±SD, 9.0±9.7,) than plaques without microcalcification (n=17, 2.9±3.8; P<0.0001). Higher 18F-NaF PET activity was associated with advanced plaques characterized by fibroatheroma (n=54, 10.7±10.3) compared with plaques with intimal thickening (n=22, 3.5±3.9) or pathological intimal thickening (n=25, 6.1±8.4; P=0.004). No significant association was found between 18F-NaF PET activity and inflammation (P=0.08).Conclusions:In ex vivo human coronary arteries, higher 18F-NaF PET activity was associated with microcalcification and advanced plaque morphology. Since microcalcification and fibroatheromas are high-risk plaque features, 18F-NaF PET/CT may improve risk-stratification.

    更新日期:2019-12-27
  • Brief Review on How to Measure Arterial Stiffness in Humans
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-26
    Patrick Segers; Ernst R. Rietzschel; Julio A. Chirinos

    Despite the wide recognition of larger artery stiffness as a highly clinically relevant and independent prognostic biomarker, it has yet be incorporated into routine clinical practice and to take a more prominent position in clinical guidelines. An important reason may be the plethora of methods and devices claiming to measure arterial stiffness in humans. This brief review provides a concise overview of methods in use, indicating strengths and weaknesses. We classified and graded methods, highly weighing their scrutiny and purity in quantifying arterial stiffness, rather than focusing on their ease of application or the level at which methods have demonstrated their prognostic and diagnostic potential.

    更新日期:2019-12-27
  • Tyrosine Kinase Inhibitors in Leukemia and Cardiovascular Events
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-26
    Ali Manouchehri; Elishama Kanu; Michael J. Mauro; Aaron W. Aday; Jonathan R. Lindner; Javid Moslehi

    Targeted oncology therapies have revolutionized cancer treatment over the last decade and have resulted in improved prognosis for many patients. This advance has emanated from elucidation of pathways responsible for tumorigenesis followed by targeting of these pathways by specific molecules. Cardiovascular care has become an increasingly critical aspect of patient care in part because patients live longer, but moreover due to potential associated toxicities from these therapies. Because of the targeted nature of cancer therapies, cardiac and vascular side effects may additionally provide insights into the basic biology of vascular disease. We herein provide the example of tyrosine kinase inhibitors utilized in chronic myelogenous leukemia to illustrate this medical transformation. We describe the vascular considerations for the clinical care of chronic myelogenous leukemia patients as well as the emerging literature on mechanisms of toxicities of the individual tyrosine kinase inhibitor. We additionally postulate that basic insights into toxicities of novel cancer therapies may serve as a new platform for investigation in vascular biology and a new translational research opportunity in vascular medicine.

    更新日期:2019-12-27
  • Macrophages in Atherosclerosis Regression
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-11-14
    Tessa J. Barrett

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    更新日期:2019-12-25
  • Impaired Regeneration Contributes to Poor Outcomes in Diabetic Peripheral Artery Disease
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-09-12
    Gian Paolo Fadini; Gaia Spinetti; Marianna Santopaolo; Paolo Madeddu

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    更新日期:2019-12-25
  • Sex Differences in Genomic Drivers of Adipose Distribution and Related Cardiometabolic Disorders
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-11-21
    Heidi S. Lumish; Marcella O’Reilly; Muredach P. Reilly

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    更新日期:2019-12-25
  • CD73 Promotes Age-Dependent Accretion of Atherosclerosis
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-17
    Nadia R. Sutton; Diane Bouïs; Kris M. Mann; Imran M. Rashid; Alexandra L. McCubbrey; Matt C. Hyman; Daniel R. Goldstein; Annie Mei; David J. Pinsky

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    更新日期:2019-12-25
  • Replacing Saturated Fat With Unsaturated Fat in Western Diet Reduces Foamy Monocytes and Atherosclerosis in Male Ldlr–/– Mice
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-17
    Zeqin Lian; Xiao-yuan Dai Perrard; Xueying Peng; Joe L. Raya; Alfredo A. Hernandez; Collin G. Johnson; William R. Lagor; Henry J. Pownall; Ron C. Hoogeveen; Scott I. Simon; Frank M. Sacks; Christie M. Ballantyne; Huaizhu Wu

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    更新日期:2019-12-25
  • TLR4 (Toll-Like Receptor 4)-Dependent Signaling Drives Extracellular Catabolism of LDL (Low-Density Lipoprotein) Aggregates
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-10
    Rajesh K. Singh; Abigail S. Haka; Arky Asmal; Valéria C. Barbosa-Lorenzi; Inna Grosheva; Harvey F. Chin; Yuquan Xiong; Timothy Hla; Frederick R. Maxfield

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    更新日期:2019-12-25
  • Plasma Kallikrein Contributes to Coagulation in the Absence of Factor XI by Activating Factor IX
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-11-26
    Mayken Visser; René van Oerle; Hugo ten Cate; Volker Laux; Nigel Mackman; Stefan Heitmeier; Henri M.H. Spronk

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    更新日期:2019-12-25
  • Short AIP1 (ASK1-Interacting Protein-1) Isoform Localizes to the Mitochondria and Promotes Vascular Dysfunction
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-17
    Zheng Li; Li Li; Haifeng Zhang; Huanjiao Jenny Zhou; Weidong Ji; Wang Min

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    更新日期:2019-12-25
  • ApoE (Apolipoprotein E) in Brain Pericytes Regulates Endothelial Function in an Isoform-Dependent Manner by Modulating Basement Membrane Components
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-31
    Yu Yamazaki; Mitsuru Shinohara; Akari Yamazaki; Yingxue Ren; Yan W. Asmann; Takahisa Kanekiyo; Guojun Bu

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    更新日期:2019-12-25
  • Endothelial GLP-1 (Glucagon-Like Peptide-1) Receptor Mediates Cardiovascular Protection by Liraglutide In Mice With Experimental Arterial Hypertension
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-11-21
    Johanna Helmstädter; Katie Frenis; Konstantina Filippou; Alexandra Grill; Mobin Dib; Sanela Kalinovic; Franziska Pawelke; Kamil Kus; Swenja Kröller-Schön; Matthias Oelze; Stefan Chlopicki; Detlef Schuppan; Philip Wenzel; Wolfram Ruf; Daniel J. Drucker; Thomas Münzel; Andreas Daiber; Sebastian Steven

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    更新日期:2019-12-25
  • Natriuretic Peptides Attenuate Retinal Pathological Neovascularization Via Cyclic Guanosine Monophosphate Signaling in Pericytes and Astrocytes
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-17
    Katarina Špiranec Spes; Sabrina Hupp; Franziska Werner; Franziska Koch; Katharina Völker; Lisa Krebes; Ulrike Kämmerer; Katrin G. Heinze; Barbara M. Braunger; Michaela Kuhn

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    更新日期:2019-12-25
  • S-Nitrosylation of Plastin-3 Exacerbates Thoracic Aortic Dissection Formation via Endothelial Barrier Dysfunction
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-11-07
    Lihong Pan; Zhe Lin; Xin Tang; Jiaxin Tian; Qiao Zheng; Jin Jing; Liping Xie; Hongshan Chen; Qiulun Lu; Hong Wang; Qingguo Li; Yi Han; Yong Ji

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    更新日期:2019-12-25
  • High Salt Intake Worsens Aortic Dissection in Mice
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-11-07
    Norifumi Nishida; Hiroki Aoki; Satoko Ohno-Urabe; Michihide Nishihara; Aya Furusho; Saki Hirakata; Makiko Hayashi; Sohei Ito; Hiroshi Yamada; Yuichiro Hirata; Hideo Yasukawa; Tsutomu Imaizumi; Hiroyuki Tanaka; Yoshihiro Fukumoto

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    更新日期:2019-12-25
  • Novel Autoimmune IgM Antibody Attenuates Atherosclerosis in IgM Deficient Low-Fat Diet–Fed, but Not Western Diet–Fed Apoe–/– Mice
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-24
    Olga A. Cherepanova; Prasad Srikakulapu; Elizabeth S. Greene; Malay Chaklader; Ryan M. Haskins; Mary E. McCanna; Smarajit Bandyopadhyay; Bhupal Ban; Norbert Leitinger; Coleen A. McNamara; Gary K. Owens

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    更新日期:2019-12-25
  • Feasibility and Clinical Significance of In Vivo Cholesterol Crystal Detection Using Optical Coherence Tomography
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-17
    Yosuke Katayama; Atsushi Tanaka; Akira Taruya; Manabu Kashiwagi; Tsuyoshi Nishiguchi; Yuichi Ozaki; Yoshiki Matsuo; Hironori Kitabata; Takashi Kubo; Emi Shimada; Toshikazu Kondo; Takashi Akasaka

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    更新日期:2019-12-25
  • Downstream Influence of Coronary Stenoses on Microcirculatory Remodeling
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-31
    Guus A. de Waard; Maurits R. Hollander; Danique Ruiter; Thomas ten Bokkel Huinink; Romain Meer; Nina W. van der Hoeven; Elisa Meinster; Jeroen A.M. Beliën; Hans W. Niessen; Niels van Royen

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    更新日期:2019-12-25
  • Extracellular Vesicles From Adipose Stem Cells Prevent Muscle Damage and Inflammation in a Mouse Model of Hind Limb Ischemia
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-31
    Federico Figliolini; Andrea Ranghino; Cristina Grange; Massimo Cedrino; Marta Tapparo; Claudia Cavallari; Andrea Rossi; Gabriele Togliatto; Saveria Femminò; Maria Vittoria Gugliuzza; Giovanni Camussi; Maria Felice Brizzi

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    更新日期:2019-12-25
  • Lipoprotein(a)-Lowering by 50 mg/dL (105 nmol/L) May Be Needed to Reduce Cardiovascular Disease 20% in Secondary Prevention
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-03
    Christian M. Madsen; Pia R. Kamstrup; Anne Langsted; Anette Varbo; Børge G. Nordestgaard

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    更新日期:2019-12-25
  • Causal Inference for Genetically Determined Levels of High-Density Lipoprotein Cholesterol and Risk of Infectious Disease
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-11-07
    Mark Trinder; Keith R. Walley; John H. Boyd; Liam R. Brunham

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    更新日期:2019-12-25
  • Intraventricular Thrombus Formation and Embolism in Takotsubo Syndrome
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-11-26
    Katharina J. Ding; Victoria L. Cammann; Konrad A. Szawan; Barbara E. Stähli; Manfred Wischnewsky; Davide Di Vece; Rodolfo Citro; Milosz Jaguszewski; Burkhardt Seifert; Annahita Sarcon; Maike Knorr; Susanne Heiner; Sebastiano Gili; Fabrizio D’Ascenzo; Michael Neuhaus; L. Christian Napp; Jennifer Franke; Michel Noutsias; Christof Burgdorf; Wolfgang Koenig; Behrouz Kherad; Lawrence Rajan; Guido Michels; Roman Pfister; Alessandro Cuneo; Claudius Jacobshagen; Mahir Karakas; Alexander Pott; Philippe Meyer; Jose D. Arroja; Adrian Banning; Florim Cuculi; Richard Kobza; Thomas A. Fischer; Tuija Vasankari; K.E. Juhani Airaksinen; Carla Paolini; Claudio Bilato; Pedro Carrilho-Ferreira; Grzegorz Opolski; Rafal Dworakowski; Philip MacCarthy; Christoph Kaiser; Stefan Osswald; Leonarda Galiuto; Wolfgang Dichtl; Christina Chan; Paul Bridgman; Clément Delmas; Olivier Lairez; Ibrahim El-Battrawy; Ibrahim Akin; Ekaterina Gilyarova; Alexandra Shilova; Mikhail Gilyarov; Martin Kozel; Petr Tousek; Petr Widimský; David E. Winchester; Jan Galuszka; Christian Ukena; John D. Horowitz; Carlo Di Mario; Abhiram Prasad; Charanjit S. Rihal; Fausto J. Pinto; Filippo Crea; Martin Borggrefe; Ruediger C. Braun-Dullaeus; Wolfgang Rottbauer; Johann Bauersachs; Hugo A. Katus; Gerd Hasenfuß; Carsten Tschöpe; Burkert M. Pieske; Holger Thiele; Heribert Schunkert; Michael Böhm; Stephan B. Felix; Thomas Münzel; Jeroen J. Bax; Thomas F. Lüscher; Frank Ruschitzka; Jelena R. Ghadri; Eduardo Bossone; Christian Templin

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    更新日期:2019-12-25
  • Ten-Year Clinical Outcomes of Late-Acquired Stent Malapposition After Coronary Stent Implantation
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-11-26
    Seung-Yul Lee; Jung-Min Ahn; Gary S. Mintz; Sung-Jin Hong; Chul-Min Ahn; Duk-Woo Park; Jung-Sun Kim; Byeong-Keuk Kim; Young-Guk Ko; Donghoon Choi; Yangsoo Jang; Seung-Jung Park; Myeong-Ki Hong

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    更新日期:2019-12-25
  • Low and Oscillatory Wall Shear Stress Is Not Related to Aortic Dilation in Patients With Bicuspid Aortic Valve
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-05
    Lydia Dux-Santoy; Andrea Guala; Julio Sotelo; Sergio Uribe; Gisela Teixidó-Turà; Aroa Ruiz-Muñoz; Daniel E. Hurtado; Filipa Valente; Laura Galian-Gay; Laura Gutiérrez; Teresa González-Alujas; Kevin M. Johnson; Oliver Wieben; Ignacio Ferreira; Arturo Evangelista; José F. Rodríguez-Palomares

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    更新日期:2019-12-25
  • MicroRNA-144 Silencing Protects Against Atherosclerosis in Male, but Not Female Mice
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-19
    Joan Cheng; Angela Cheng; Bethan L. Clifford; Xiaohui Wu; Ulf Hedin; Lars Maegdefessel; Nathalie Pamir; Tamer Sallam; Elizabeth J. Tarling; Thomas Q. de Aguiar Vallim

    Objective:Atherosclerosis is a leading cause of death in developed countries. MicroRNAs act as fine-tuners of gene expression and have been shown to have important roles in the pathophysiology and progression of atherosclerosis. We, and others, previously demonstrated that microRNA-144 (miR-144) functions to post-transcriptionally regulate ABCA1 (ATP binding cassette transporter A1) and plasma HDL (high-density lipoprotein) cholesterol levels. Here, we explore how miR-144 inhibition may protect against atherosclerosis.Approach and Results:We demonstrate that miR-144 silencing reduced atherosclerosis in male, but not female low-density lipoprotein receptor null (Ldlr−/−) mice. MiR-144 antagonism increased circulating HDL cholesterol levels, remodeled the HDL particle, and enhanced reverse cholesterol transport. Notably, the effects on HDL and reverse cholesterol transport were more pronounced in male mice suggesting sex-specific differences may contribute to the effects of silencing miR-144 on atherosclerosis. As a molecular mechanism, we identify the oxysterol metabolizing enzyme CYP7B1 (cytochrome P450 enzyme 7B1) as a miR-144 regulated gene in male, but not female mice. Consistent with miR-144-dependent changes in CYP7B1 activity, we show decreased levels of 27-hydroxycholesterol, a known proatherogenic sterol and the endogenous substrate for CYP7B1 in male, but not female mice.Conclusions:Our data demonstrate silencing miR-144 has sex-specific effects and that treatment with antisense oligonucleotides to target miR-144 might result in enhancements in reverse cholesterol transport and oxysterol metabolism in patients with cardiovascular disease.

    更新日期:2019-12-19
  • IL (Interleukin)-6 Contributes to Deep Vein Thrombosis and Is Negatively Regulated by miR-338-5p
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-19
    Yunhong Zhang; Zhen Zhang; Ran Wei; Xiuming Miao; Shangwen Sun; Gang Liang; Chu Chu; Lin Zhao; Xiaoxiao Zhu; Qiang Guo; Bin Wang; Xia Li

    Objective:Deep venous thrombosis (DVT), one of the most common venous thromboembolic disorders, is closely linked with pulmonary embolism and post-thrombotic syndrome, both of which have a high mortality. However, the factors that trigger DVT formation are still largely unknown. Elevated expression of IL (interleukin)-6—an important inflammatory cytokine—has been linked with DVT formation. However, the molecular mechanisms leading to the elevated IL-6 in DVT remain unclear. Here, we proposed that epigenetic modification of IL-6 at the post-transcriptional level may be a crucial trigger for IL-6 upregulation in DVT.Approach and Results:To explore the association between microRNAs and IL-6 in DVT, we performed microRNA microarray analysis and experiments both in vitro and in vivo. Microarray and quantitative real-time polymerase chain reaction results showed that IL-6 expression was increased while miR-338-5p level was decreased substantially in peripheral blood mononuclear cells of patients with DVT, and there was significant negative correlation between miR-338-5p and IL-6. Experiments in vitro showed that overexpressed miR-338-5p reduced IL-6 expression, while miR-338-5p knockdown increased IL-6 expression. Moreover, our in vivo study found that mice with anti–IL-6 antibody or agomiR-338-5p delivery resulted in decreased IL-6 expression and alleviated DVT formation, whereas antagomiR-338-5p acted inversely. Most of miR-338-5p was found located in cytoplasm by fluorescence in situ hybridization. Dual-luciferase reporter assay identified direct binding between miR-338-5p and IL-6.Conclusions:Our results suggest that decreased miR-338-5p promotes DVT formation by increasing IL-6 expression.

    更新日期:2019-12-19
  • Proinflammatory Mediators, IL (Interleukin)-1β, TNF (Tumor Necrosis Factor) α, and Thrombin Directly Induce Capillary Tube Regression
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-19
    Gretchen M. Koller; Christopher Schafer; Scott S. Kemp; Kalia N. Aguera; Prisca K. Lin; Joshua C. Forgy; Courtney T. Griffin; George E. Davis

    Objective:In this work, we examine the molecular basis for capillary tube regression and identify key proregressive factors, signaling pathways, and pharmacological antagonists of this process.Approach and Results:We demonstrate that the proinflammatory mediators, IL (interleukin)-1β, TNF (tumor necrosis factor) α, and thrombin, singly and in combination, are potent regulators of capillary tube regression in vitro. These proregressive factors, when added to endothelial cell–pericyte cocultures, led to selective loss of endothelial cell-lined tube networks, with retention and proliferation of pericytes despite the marked destruction of adjacent capillary tubes. Moreover, treatment of macrophages with the TLR (toll-like receptor) agonists Pam3CSK4 and lipopolysaccharide generates conditioned media with marked proregressive activity, that is completely blocked by a combination of neutralizing antibodies directed to IL-1β and TNFα but not to other factors. The same combination of blocking antibodies, as well as the anti-inflammatory cytokine IL-10, interfere with macrophage-dependent hyaloid vasculature regression in mice suggesting that proinflammatory cytokine signaling regulates capillary regression in vivo. In addition, we identified a capillary regression signaling signature in endothelial cells downstream of these proregressive agents that is characterized by increased levels of ICAM-1, phospho-p38, and phospho-MLC2 and decreased levels of phospho-Pak2, acetylated tubulin, phospho-cofilin, and pro-caspase3. Finally, we identified combinations of pharmacological agents (ie, FIST and FISTSB) that markedly rescue the proregressive activities of IL-1β, TNFα, and thrombin, individually and in combination.Conclusions:Overall, these new studies demonstrate that the major proinflammatory mediators, IL-1β, TNFα, and thrombin, are key regulators of capillary tube regression—a critical pathological process regulating human disease.

    更新日期:2019-12-19
  • Plasma Albumin and Incident Cardiovascular Disease
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-19
    Andreas Ronit; Ditte M. Kirkegaard-Klitbo; Tine L. Dohlmann; Jens Lundgren; Caroline A. Sabin; Andrew N. Phillips; Børge G. Nordestgaard; Shoaib Afzal

    Objective:We studied the association of plasma albumin with cardiovascular disease (CVD) and explored potential mechanisms behind the association in the CGPS (Copenhagen General Population Study). We also performed a meta-analysis to summarize the association between plasma albumin and CVD in individuals without preexisting CVD.Approach and Results:We included 100 520 individuals without prior CVD with 8247 incident CVD events developed during a median follow-up of 8.5 years. Rates of CVD outcomes were calculated using Cox regression and Fine and Gray competing-risks regression. The association of plasma albumin and CVD was approximately linear and confounder adjustment had little influence on the effect estimates, except for some attenuation after CRP (C-reactive protein) adjustment. In analyses according to subtypes of CVD events, the hazard ratios for each 10 g/L lower plasma albumin were 1.17 (95% CI, 1.08–1.28) for ischemic heart disease, 1.25 (95% CI, 1.09–1.43) for myocardial infarction, 1.37 (95% CI, 1.21–1.54) for any stroke, and 1.46 (95% CI, 1.28–1.68) for ischemic stroke. In the meta-analysis, we combined estimates from prospective and nested case-control studies investigating the association of plasma albumin with CVD. The meta-analysis included 14 studies with 150 652 individuals (12 studies reported events totaling 11 872). The risk ratio for a CVD event per 10 g/L lower plasma albumin was 1.96 (95% CI, 1.43–2.68) in previous studies and 1.85 (95% CI, 1.39–2.47) including our study with 57% weight in the meta-analysis. Exploratory analyses of the mechanism of the association indicated that it was probably not due to fatty acid binding but may be due to the regulation of plasma albumin by inflammation.Conclusions:There is a robust, independent association of low plasma albumin with CVD, partly explained by plasma albumin as a negative acute-phase reactant.Clinical Trial Registration:URL: Unique identifier: CRD42018095796

    更新日期:2019-12-19
  • Retinoids Repress Human Cardiovascular Cell Calcification With Evidence for Distinct Selective Retinoid Modulator Effects
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-19
    Maximillian A. Rogers; Jiaohua Chen; Shriram Nallamshetty; Tan Pham; Shinji Goto; Jochen D. Muehlschlegel; Peter Libby; Masanori Aikawa; Elena Aikawa; Jorge Plutzky

    Objective:Retinoic acid (RA) is a ligand for nuclear receptors that modulate gene transcription and cell differentiation. Whether RA controls ectopic calcification in humans is unknown. We tested the hypothesis that RA regulates osteogenic differentiation of human arterial smooth muscle cells and aortic valvular interstitial cells that participate in atherosclerosis and heart valve disease, respectively.Approach and Results:Human cardiovascular tissue contains immunoreactive RAR (RA receptor)—a retinoid-activated nuclear receptor directing multiple transcriptional programs. RA stimulation suppressed primary human cardiovascular cell calcification while treatment with the RAR inhibitor AGN 193109 or RARα siRNA increased calcification. RA attenuated calcification in a coordinated manner, increasing levels of the calcification inhibitor MGP (matrix Gla protein) while decreasing calcification-promoting TNAP (tissue nonspecific alkaline phosphatase) activity. Given that nuclear receptor action varies as a function of distinct ligand structures, we compared calcification responses to cyclic retinoids and the acyclic retinoid peretinoin. Peretinoin suppressed human cardiovascular cell calcification without inducing either secretion of APOC3 (apolipoprotein-CIII), which promotes atherogenesis, or reducing CYP7A1 (cytochrome P450 family 7 subfamily A member 1) expression, which occurred with cyclic retinoids all-trans RA, 9-cis RA, and 13-cis RA. Additionally, peretinoin did not suppress human femur osteoblast mineralization, whereas all-trans RA inhibited osteoblast mineralization.Conclusions:These results establish retinoid regulation of human cardiovascular calcification, provide new insight into mechanisms involved in these responses, and suggest selective retinoid modulators, like acyclic retinoids may allow for treating cardiovascular calcification without the adverse effects associated with cyclic retinoids.

    更新日期:2019-12-19
  • PTEN (Phosphatase and Tensin Homolog) Protects Against Ang II (Angiotensin II)-Induced Pathological Vascular Fibrosis and Remodeling
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-19
    Sizhao Lu; Keith A. Strand; Marie F. Mutryn; Rebecca M. Tucker; Austin J. Jolly; Seth B. Furgeson; Karen S. Moulton; Raphael A. Nemenoff; Mary C.M. Weiser-Evans

    Objective:Pathological vascular remodeling and excessive perivascular fibrosis are major contributors to reduced vessel compliance that exacerbates cardiovascular diseases, for instance, promoting clinically relevant myocardial remodeling. Inflammation plays a significant role in both pathological vascular remodeling and fibrosis. We previously demonstrated that smooth muscle cell–specific PTEN depletion promotes significant vascular fibrosis and accumulation of inflammatory cells. In the current study, we aimed to determine the beneficial role of systemic PTEN elevation on Ang II (angiotensin II)-induced vascular fibrosis and remodeling.Approach and Results:Transgenic mice carrying additional copies of the wild-type Pten gene (super PTEN [sPTEN]) and WT littermates were subjected to Ang II or saline infusion for 14 or 28 days. Compared with WT, Ang II-induced vascular fibrosis was significantly blunted in sPTEN mice, as shown by histochemical stainings and label-free second harmonic generation imaging. The protection against Ang II was recapitulated in sPTEN mice bearing WT bone marrow but not in WT mice reconstituted with sPTEN bone marrow. Ang II-induced elevation of profibrotic and proinflammatory gene expression observed in WT mice was blocked in aortic tissue of sPTEN mice. Immunofluorescent staining and flow cytometry both indicated that perivascular infiltration of T cells and macrophages was significantly inhibited in sPTEN mice. In vitro induction of PTEN expression suppressed Ang II-induced Ccl2 expression in vascular smooth muscle cells.Conclusions:Systemic PTEN elevation mediates protection against Ang II-induced vascular inflammation and fibrosis predominantly through effects in resident vascular cells. Our data highly support that pharmacological upregulation of PTEN could be a novel and viable approach for the treatment of pathological vascular fibrosis.

    更新日期:2019-12-19
  • 2019 Russell Ross Memorial Lecture in Vascular Biology
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-19
    Aditi Upadhye; Jeffrey M. Sturek; Coleen A. McNamara

    Atherosclerosis—the major underlying pathology of cardiovascular disease—is characterized by accumulation and subsequent oxidative modification of lipoproteins within the artery wall, leading to inflammatory cell infiltration and lesion formation that can over time result in arterial stenosis, ischemia, and downstream adverse events. The contribution of innate and adaptive immunity to atherosclerosis development is well established, and B cells have emerged as important modulators of both pro- and anti-inflammatory effects in atherosclerosis. Murine B cells can broadly be divided into 2 subsets: (1) B-2 cells, which are bone marrow derived and include conventional follicular and marginal zone B cells, and (2) B-1 cells, which are largely fetal liver derived and persist in adults through self-renewal. B-cell subsets are developmentally, functionally, and phenotypically distinct with unique subset-specific contributions to atherosclerosis development. Mechanisms whereby B cells regulate vascular inflammation and atherosclerosis will be discussed with a particular emphasis on B-1 cells. B-1 cells have a protective role in atherosclerosis that is mediated in large part by IgM antibody production. Accumulating evidence over the last several years has pointed to a previously underappreciated heterogeneity in B-1 cell populations, which may have important implications for understanding atherosclerosis development and potential targeted therapeutic approaches. This heterogeneity within atheroprotective innate B-cell subsets will be highlighted.

    更新日期:2019-12-19
  • Shear Stress Regulation of Endothelial Glycocalyx Structure Is Determined by Glucobiosynthesis
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-12
    Gangqi Wang; Sarantos Kostidis; Gesa L. Tiemeier; Wendy M.P.J. Sol; Margreet R. de Vries; Martin Giera; Peter Carmeliet; Bernard M. van den Berg; Ton J. Rabelink

    Objective:Endothelial cells exposed to laminar shear stress express a thick glycocalyx on their surface that plays an important role in reducing vascular permeability and endothelial anti-inflammatory, antithrombotic, and antiangiogenic properties. Production and maintenance of this glycocalyx layer is dependent on cellular carbohydrate synthesis, but its regulation is still unknown.Approach and Results:Here, we show that biosynthesis of the major structural component of the endothelial glycocalyx, hyaluronan, is regulated by shear. Both in vitro as well as in in vivo, hyaluronan expression on the endothelial surface is increased on laminar shear and reduced when exposed to oscillatory flow, which is regulated by KLF2 (Krüppel-like Factor 2). Using a CRISPR-CAS9 edited small tetracysteine tag to endogenous HAS2 (hyaluronan synthase 2), we demonstrated increased translocation of HAS2 to the endothelial cell membrane during laminar shear. Hyaluronan production by HAS2 was shown to be further driven by availability of the hyaluronan substrates UDP-glucosamine and UDP-glucuronic acid. KLF2 inhibits endothelial glycolysis and allows for glucose intermediates to shuttle into the hexosamine- and glucuronic acid biosynthesis pathways, as measured using nuclear magnetic resonance analysis in combination with 13C-labeled glucose.Conclusions:These data demonstrate how endothelial glycocalyx function and functional adaptation to shear is coupled to KLF2-mediated regulation of endothelial glycolysis.

    更新日期:2019-12-13
  • Novel Plaque Enriched Long Noncoding RNA in Atherosclerotic Macrophage Regulation (PELATON)
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-12
    John Hung; Jessica P. Scanlon; Amira D. Mahmoud; Julie Rodor; Margaret Ballantyne; Margaux A.C. Fontaine; Lieve Temmerman; Jakub Kaczynski; Katie L. Connor; Raghu Bhushan; Erik A.L. Biessen; David E. Newby; Judith C. Sluimer; Andrew H. Baker

    Objective:Long noncoding RNAs (lncRNAs) are an emergent class of molecules with diverse functional roles, widely expressed in human physiology and disease. Although some lncRNAs have been identified in cardiovascular disease, their potential as novel targets in the prevention of atherosclerosis is unknown. We set out to discover important lncRNAs in unstable plaque and gain insight into their functional relevance.Approach and Results:Analysis of RNA sequencing previously performed on stable and unstable atherosclerotic plaque identified a panel of 47 differentially regulated lncRNAs. We focused on LINC01272, a lncRNA upregulated in unstable plaque previously detected in inflammatory bowel disease, which we termed PELATON (plaque enriched lncRNA in atherosclerotic and inflammatory bowel macrophage regulation). Here, we demonstrate that PELATON is highly monocyte- and macrophage-specific across vascular cell types, and almost entirely nuclear by cellular fractionation (90%–98%). In situ hybridization confirmed enrichment of PELATON in areas of plaque inflammation, colocalizing with macrophages around the shoulders and necrotic core of human plaque sections. Consistent with its nuclear localization, and despite containing a predicted open reading frame, PELATON did not demonstrate any protein-coding potential in vitro. Functionally, knockdown of PELATON significantly reduced phagocytosis, lipid uptake and reactive oxygen species production in high-content analysis, with a significant reduction in phagocytosis independently validated. Furthermore, CD36, a key mediator of phagocytic oxLDL (oxidized low-density lipoprotein) uptake was significantly reduced with PELATON knockdown.Conclusions:PELATON is a nuclear expressed, monocyte- and macrophage-specific lncRNA, upregulated in unstable atherosclerotic plaque. Knockdown of PELATON affects cellular functions associated with plaque progression.

    更新日期:2019-12-13
  • Intercellular Conduction Optimizes Arterial Network Function and Conserves Blood Flow Homeostasis During Cerebrovascular Challenges
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-12
    Anil Zechariah; Cam Ha T. Tran; Bjorn O. Hald; Shaun L. Sandow; Maria Sancho; Michelle Sun Mi Kim; Sergio Fabris; Ursula I. Tuor; Grant R.J. Gordon; Donald G. Welsh

    Objective:Cerebral arterial networks match blood flow delivery with neural activity. Neurovascular response begins with a stimulus and a focal change in vessel diameter, which by themselves is inconsequential to blood flow magnitude, until they spread and alter the contractile status of neighboring arterial segments. We sought to define the mechanisms underlying integrated vascular behavior and considered the role of intercellular electrical signaling in this phenomenon.Approach and Results:Electron microscopic and histochemical analysis revealed the structural coupling of cerebrovascular cells and the expression of gap junctional subunits at the cell interfaces, enabling intercellular signaling among vascular cells. Indeed, robust vasomotor conduction was detected in human and mice cerebral arteries after focal vessel stimulation: a response attributed to endothelial gap junctional communication, as its genetic alteration attenuated this behavior. Conducted responses were observed to ascend from the penetrating arterioles, influencing the contractile status of cortical surface vessels, in a simulated model of cerebral arterial network. Ascending responses recognized in vivo after whisker stimulation were significantly attenuated in mice with altered endothelial gap junctional signaling confirming that gap junctional communication drives integrated vessel responses. The diminishment in vascular communication also impaired the critical ability of the cerebral vasculature to maintain blood flow homeostasis and hence tissue viability after stroke.Conclusions:Our findings highlight the integral role of intercellular electrical signaling in transcribing focal stimuli into coordinated changes in cerebrovascular contractile activity and expose, a hitherto unknown mechanism for flow regulation after stroke.

    更新日期:2019-12-13
  • Interference With ESAM (Endothelial Cell-Selective Adhesion Molecule) Plus Vascular Endothelial-Cadherin Causes Immediate Lethality and Lung-Specific Blood Coagulation
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-12
    Cao Nguyen Duong; Astrid F. Nottebaum; Stefan Butz; Stefan Volkery; Dagmar Zeuschner; Martin Stehling; Dietmar Vestweber

    Objective:Vascular endothelial (VE)-cadherin is of dominant importance for the formation and stability of endothelial junctions, yet induced gene inactivation enhances vascular permeability in the lung but does not cause junction rupture. This study aims at identifying the junctional adhesion molecule, which is responsible for preventing endothelial junction rupture in the pulmonary vasculature in the absence of VE-cadherin.Approach and Results:We have compared the relevance of ESAM (endothelial cell-selective adhesion molecule), JAM (junctional adhesion molecule)-A, PECAM (platelet endothelial cell adhesion molecule)-1, and VE-cadherin for vascular barrier integrity in various mouse tissues. Gene inactivation of ESAM enhanced vascular permeability in the lung but not in heart, skin, and brain. In contrast, deletion of JAM-A or PECAM-1 did not affect barrier integrity in any of these organs. Blocking VE-cadherin with antibodies caused lethality in ESAM−/− mice within 30 minutes but had no such effect in JAM-A−/−, PECAM-1−/− or wild-type mice. Likewise, induced gene inactivation of VE-cadherin caused rapid lethality only in the absence of ESAM. Ultrastructural analysis revealed that only combined interference with VE-cadherin and ESAM disrupted endothelial junctions and caused massive blood coagulation in the lung. Mechanistically, we could exclude a role of platelet ESAM in coagulation, changes in the expression of other junctional proteins or a contribution of cytoplasmic signaling domains of ESAM.Conclusions:Despite well-documented roles of JAM-A and PECAM-1 for the regulation of endothelial junctions, only for ESAM we detected an essential role for endothelial barrier integrity in a tissue-specific way. In addition, we found that it is ESAM which prevents endothelial junction rupture in the lung when VE-cadherin is absent.

    更新日期:2019-12-13
  • Carotid Intima-Media Thickness
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-05
    Rona J. Strawbridge, Joey Ward, Mark E.S. Bailey, Breda Cullen, Amy Ferguson, Nicholas Graham, Keira J.A. Johnston, Laura M. Lyall, Robert Pearsall, Jill Pell, Richard J. Shaw, Rachana Tank, Donald M. Lyall, Daniel J. Smith

    Objective:Atherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultrasound measurement of the carotid intima-media thickness (cIMT) can be used to measure vascular remodeling, which is indicative of atherosclerosis. Genome-wide association studies have identified many genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here, we conducted genome-wide association analyses in UKB (UK Biobank; N=22 179), the largest single study with consistent cIMT measurements.Approach and Results:We used BOLT-LMM to run linear regression of cIMT in UKB, adjusted for age, sex, and genotyping chip. In white British participants, we identified 5 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a locus on chromosome 5, associated with cIMT in women only and highlight VCAN as a good candidate gene at this locus. Genetic correlations with body mass index and glucometabolic traits were also observed. Two loci influenced risk of ischemic heart disease.ConclusionS:These findings replicate previously reported associations, highlight novel biology, and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression.

    更新日期:2019-12-05
  • Netrin-1 and the Grade of Atherosclerosis Are Inversely Correlated in Humans
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-05
    Caroline S. Bruikman, Dianne Vreeken, Renate M. Hoogeveen, Michiel J. Bom, Ibrahim Danad, Sara-Joan Pinto-Sietsma, Anton Jan van Zonneveld, Paul Knaapen, G. Kees Hovingh, Erik S.G. Stroes, Janine M. van Gils

    Objective:Netrin-1 has been shown to play a role in the initiation of atherosclerosis in mice models. However, little is known about the role of Netrin-1 in humans. We set out to study whether Netrin-1 is associated with different stages of atherosclerosis.Approach and Results:Plasma Netrin-1 levels were measured in different patient cohorts: (1) 22 patients with high cardiovascular risk who underwent arterial wall inflammation assessment using positron-emission tomography / computed tomography, (2) 168 patients with a positive family history of premature atherosclerosis in whom coronary artery calcium scores were obtained, and (3) 104 patients with chest pain who underwent coronary computed tomography angiography imaging to evaluate plaque vulnerability and burden. Netrin-1 plasma levels were negatively correlated with arterial wall inflammation (β, −0.01 [95% CI, 0.02 to −0.01] R2, 0.61; P<0.0001), and concentrations of Netrin-1 were significantly lower when atherosclerosis was present compared with individuals without atherosclerosis (28.01 versus 10.51 ng/mL, P<0.001). There was no difference in Netrin-1 plasma concentrations between patients with stable versus unstable plaques (11.17 versus 11.74 ng/mL, P=0.511). However, Netrin-1 plasma levels were negatively correlated to total plaque volume (β, −0.09 [95% CI, −0.11 to −0.08] R2, 0.57, P<0.0001), calcified plaque volumes (β, −0.10 [95% CI, −0.12 to −0.08] R2, 0.53; P<0.0001), and noncalcified plaque volumes (β, −0.08 [95% CI, −0.10 to −0.06] R2, 0.41; P<0.0001). Treatment of inflammatory stimulated endothelial cells with plasma with high Netrin-1 level resulted in reduced endothelial inflammation and consequently, less monocyte adhesion.ConclusionS:Netrin-1 plasma levels are lower in patients with subclinical atherosclerosis and in patients with arterial wall inflammation. Netrin-1 is not associated with plaque vulnerability; however, it is negatively correlated to plaque burden, suggesting that Netrin-1 is involved in some, but not all, stages of atherosclerosis.

    更新日期:2019-12-05
  • Low Levels of CD4+CD28null T Cells at Baseline Are Associated With First-Time Coronary Events in a Prospective Population-Based Case-Control Cohort
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-05
    Lukas Tomas, Eva Bengtsson, Linda Andersson, Wiaam Badn, Christoffer Tengryd, Ana Persson, Andreas Edsfeldt, Peter M. Nilsson, Alexandru Schiopu, Jan Nilsson, Isabel Gonçalves, Harry Björkbacka

    Objective:CD4+CD28null T cells have been shown to be associated with recurrent coronary events and suggested as potential biomarkers and therapeutic targets. It is unknown whether CD4+CD28null T cells associate with first-time cardiovascular events. We examined CD4+CD28null T cells in a prospective population-based cohort and in patients with advanced atherosclerosis.Approach and Results:CD4+CD28null T cells were quantified in 272 individuals experiencing a first-time coronary event during up to 17 years of follow-up and 272 age- and sex-matched controls in a case-control study, nested within the population-based Malmö Diet and Cancer study. The highest tertile of CD4+CD28null T cells was associated with a lower incidence of first-time coronary events compared with the lowest tertile (odds ratio, 0.48 [95% CI, 0.29–0.79] P=0.004) when adjusting for Framingham risk factors. This association remained significant for events recorded after >9 years of follow-up, when most coronary events occurred, but not during the first 9 years of follow-up, despite similar odds ratio. Additionally, we analyzed CD4+CD28null T cells in 201 patients with advanced atherosclerosis undergoing carotid endarterectomy. The adjusted hazard ratio for cardiovascular events in patients with advanced atherosclerosis was 2.11 (95% CI, 1.10–4.05, P=0.024), comparing the highest with the lowest CD4+CD28null T-cell tertile.Conclusions:Our findings reveal complex associations between CD4+CD28null T cells and cardiovascular disease. Although we confirm the reported positive associations with an adverse prognosis in patients with already established disease, the opposite associations with first-time coronary events in the population-based cohort may limit the clinical use of CD4+CD28null T cells.

    更新日期:2019-12-05
  • Causal Associations Between Serum Bilirubin Levels and Decreased Stroke Risk
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-12-05
    Yoonjeong Choi, Sun Ju Lee, Wes Spiller, Keum Ji Jung, Ji-Young Lee, Heejin Kimm, Joung Hwan Back, Sunmi Lee, Sun Ha Jee

    Objective:A number of epidemiological studies have reported that decreased serum bilirubin, an endogenous antioxidant, is associated with cardiovascular disease. However, previous Mendelian randomization analyses conducted using a single sample have shown no evidence of association.Approach and Results:A 2-sample summary Mendelian randomization study was performed by obtaining exposure and outcome data from separate nonoverlapping samples. We utilized data from the KoGES (Korean Genome and Epidemiology Study; n=25 406) and KCPS-II (Korean Cancer Prevention Study-II; n=14 541) biobank for serum bilirubin and stroke, respectively. Using KoGES, a total of 1784 single nucleotide polymorphisms associated with serum bilirubin levels were discovered using a genome-wide significance threshold (P<5×10−8), of which 10 single nucleotide polymorphisms were identified as independent (R2<0.005) and adopted as genetic instruments. From KCPS-II, total and ischemic stroke cases were identified (n=1489 and n=686), with 12 366 acting as controls. Various 2-sample summary Mendelian randomization methods were employed, with Mendelian randomization estimates showing an inverse causal association between serum bilirubin levels and total stroke risk (odds ratio, 0.481 [95% CI, 0.234–0.988]; P=0.046). This association increased in magnitude when restricting the analysis to ischemic stroke cases (odds ratio, 0.302 [95% CI, 0.105–0.868]; P=0.026).Conclusions:Our findings provide evidence of significant causal relationship between high levels of bilirubin and decreased stroke risk in Korean population in agreement with observational approaches. This highlights the potential for bilirubin to serve as a therapeutic target for oxidative stress-related diseases such as stroke and suggests that previous findings were not a consequence of unmeasured confounding.

    更新日期:2019-12-05
  • Proceedings of the Ninth HDL (High-Density Lipoprotein) Workshop
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-10
    Annabelle Rodriguez, Bernardo L. Trigatti, Chieko Mineo, Darcy Knaack, John T. Wilkins, Daisy Sahoo, Bela F. Asztalos, Samia Mora, Marina Cuchel, Henry J. Pownall, Corina Rosales, Pascal Bernatchez, Amanda Ribeiro Martins da Silva, Godfrey S. Getz, Jacob L. Barber, Gregory C. Shearer, Angela M. Zivkovic, Uwe J.F. Tietge, Frank M. Sacks, Margery A. Connelly, Michael N. Oda, W. Sean Davidson, Mary G. Sorci-Thomas, Tomas Vaisar, Giacomo Ruotolo, Kasey C. Vickers, Catherine Martel

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    更新日期:2019-11-27
  • IDOL G51S Variant Is Associated With High Blood Cholesterol and Increases Low-Density Lipoprotein Receptor Degradation
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-10
    Dilare Adi, Xiao-Yi Lu, Zhen-Yan Fu, Jian Wei, Gulinaer Baituola, Ya-Jie Meng, Yu-Xia Zhou, Ao Hu, Jin-Kai Wang, Xiang-Feng Lu, Yan Wang, Bao-Liang Song, Yi-Tong Ma, Jie Luo

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    更新日期:2019-11-27
  • Functional Characterization of LIPA (Lysosomal Acid Lipase) Variants Associated With Coronary Artery Disease
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-24
    Trent D. Evans, Xiangyu Zhang, Reece E. Clark, Arturo Alisio, Eric Song, Hanrui Zhang, Muredach P. Reilly, Nathan O. Stitziel, Babak Razani

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    更新日期:2019-11-27
  • Extracellular MicroRNA-92a Mediates Endothelial Cell–Macrophage Communication
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-10
    Ya-Ju Chang, Yi-Shuan Li, Chia-Ching Wu, Kuei-Chun Wang, Tzu-Chieh Huang, Zhen Chen, Shu Chien

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    更新日期:2019-11-27
  • HIMF (Hypoxia-Induced Mitogenic Factor) Signaling Mediates the HMGB1 (High Mobility Group Box 1)-Dependent Endothelial and Smooth Muscle Cell Crosstalk in Pulmonary Hypertension
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-10
    Qing Lin, Chunling Fan, Jose Gomez-Arroyo, Katrien Van Raemdonck, Lucas W. Meuchel, John T. Skinner, Allen D. Everett, Xia Fang, Andrew A. Macdonald, Kazuyo Yamaji-Kegan, Roger A. Johns

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    更新日期:2019-11-27
  • Anti-Inflammatory Effects of HDL (High-Density Lipoprotein) in Macrophages Predominate Over Proinflammatory Effects in Atherosclerotic Plaques
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-03
    Panagiotis Fotakis, Vishal Kothari, David G. Thomas, Marit Westerterp, Matthew M. Molusky, Elissa Altin, Sandra Abramowicz, Nan Wang, Yi He, Jay W. Heinecke, Karin E. Bornfeldt, Alan R. Tall

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    更新日期:2019-11-27
  • Myocardin-Dependent Kv1.5 Channel Expression Prevents Phenotypic Modulation of Human Vessels in Organ Culture
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-10
    Marycarmen Arévalo-Martínez, Pilar Cidad, Nadia García-Mateo, Sara Moreno-Estar, Julia Serna, Mirella Fernández, Karl Swärd, María Simarro, Miguel A. de la Fuente, José R. López-López, M. Teresa Pérez-García

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    更新日期:2019-11-27
  • Ultrasound Molecular Imaging of Atherosclerosis With Nanobodies
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-10
    Mukesh Punjabi, Lifen Xu, Amanda Ochoa-Espinosa, Alexandra Kosareva, Thomas Wolff, Ahmed Murtaja, Alexis Broisat, Nick Devoogdt, Beat A. Kaufmann

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    更新日期:2019-11-27
  • Spectrum of Mutations and Long-Term Clinical Outcomes in Genetic Chylomicronemia Syndromes
    Arterioscler. Thromb. Vasc. Biol. (IF 6.618) Pub Date : 2019-10-17
    Laura D’Erasmo, Alessia Di Costanzo, Francesca Cassandra, Ilenia Minicocci, Luca Polito, Anna Montali, Fabrizio Ceci, Marcello Arca

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    更新日期:2019-11-27
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