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Smooth Muscle Cells in Vascular Remodeling. 血管重构中的平滑肌细胞。
Pub Date : 2019-11-26 DOI: 10.1161/ATVBAHA.119.312581
Ning Shi, Xiaohan Mei, Shi-You Chen
As the primary causes of myocardial infarction, stroke, atherosclerosis, in-stent restenosis, and aneurysm, aortic diseases pose a serious threat to human health. Arterial remodeling is considered to be an important mechanism underlying the development of arterial diseases. Arterial remodeling refers to structural and functional alterations in arterial wall in response to vascular injury or aging. Vascular smooth muscle cells (SMCs), a major component of the arterial wall, exhibit remarkable phenotypic plasticity and can dedifferentiate from a contractile state to a synthetic state, along with increased proliferation and migration abilities.1 Phenotypically modified SMCs play a major role in arterial remodeling.1 Recent publications in ATVB have delineated new pathways or factors that are involved in SMC phenotypic modulation and arterial remodeling. These studies have provided valuable insights for better understanding of regulatory mechanisms responsible for vascular remodeling. This article highlights studies on this topic that have published in ATVB recently.
主动脉疾病是导致心肌梗死、脑卒中、动脉粥样硬化、支架内再狭窄、动脉瘤的主要原因,严重威胁着人类的健康。动脉重塑被认为是动脉疾病发生的重要机制。动脉重构是指血管损伤或老化导致的动脉壁结构和功能改变。血管平滑肌细胞(SMCs)是动脉壁的主要组成部分,表现出显著的表型可塑性,可以从收缩状态向合成状态去分化,同时增殖和迁移能力增强表型修饰的SMCs在动脉重塑中起主要作用最近发表在ATVB上的文章描述了参与SMC表型调节和动脉重塑的新途径或因素。这些研究为更好地理解血管重构的调控机制提供了有价值的见解。本文重点介绍了最近在ATVB上发表的关于这一主题的研究。
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引用次数: 44
Myocardin and Kv1 Channels: A Paradigm Shift in Treating Vascular Smooth Muscle Cell-Related Proliferative Disease? 心肌素和Kv1通道:治疗血管平滑肌细胞相关增生性疾病的范式转变?
Pub Date : 2019-11-26 DOI: 10.1161/ATVBAHA.119.313531
David X. Zhang, D. Gutterman
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引用次数: 1
Ten-Year Clinical Outcomes of Late-Acquired Stent Malapposition After Coronary Stent Implantation. 冠状动脉支架植入术后迟发性支架错位10年临床观察。
Pub Date : 2019-11-26 DOI: 10.1161/ATVBAHA.119.313602
Seung‐Yul Lee, Jung‐Min Ahn, G. Mintz, Sung‐Jin Hong, C. Ahn, Duk‐Woo Park, Jung‐Sun Kim, Byeong‐Keuk Kim, Y. Ko, D. Choi, Y. Jang, Seung‐Jung Park, M. Hong
OBJECTIVEThe goal of this study was to determine the impact of late-acquired stent malapposition (LASM) on long-term clinical outcomes in patients treated with coronary stent implantation. Approach and Results: We investigated major adverse cardiac event during 10 years after 6-month intravascular ultrasound examination using our previous studies database. A total of 732 patients treated with bare-metal stent (54 LASM versus 678 non-LASM) and 529 patients treated with first-generation drug-eluting stent (82 LASM versus 447 non-LASM), who did not have clinical event or censoring at the time of follow-up intravascular ultrasound, were included for the present analysis. major adverse cardiac event was defined as the composite of cardiac death, target vessel-related myocardial infarction, target lesion revascularization and stent thrombosis. Multivariable adjustment and inverse probability weight were performed to consider baseline differences. After multivariable adjustment, LASM was related to a greater risk of major adverse cardiac event (hazard ratio, 1.666 [95% CI, 1.041-2.665]; P=0.0333) and very-late stent thrombosis (hazard ratio, 3.529 [95% CI, 1.153-10.798]; P=0.0271) than non-LASM in patients treated with first-generation drug-eluting stent, but not in those treated with bare-metal stent. Results were consistent after inverse probability weight. Among patients with LASM of first-generation drug-eluting stent, no late stent thrombosis occurred in patients who continued to receive dual antiplatelet therapy.CONCLUSIONSThe relationship between LASM and major adverse cardiac event might depend on the type of implanted stents during the long-term follow-up, highlighting the clinical significance of polymers and drugs in drug-eluting stent system.
目的本研究的目的是确定晚期获得性支架错位(LASM)对冠状动脉支架植入术患者长期临床结果的影响。方法和结果:我们利用先前的研究数据库,在6个月血管内超声检查后,调查了10年内主要的不良心脏事件。本研究共纳入732例裸金属支架患者(54例LASM vs 678例非LASM)和529例第一代药物洗脱支架患者(82例LASM vs 447例非LASM),这些患者在随访血管内超声时没有临床事件或检查。主要心脏不良事件定义为心源性死亡、靶血管相关性心肌梗死、靶病变血运重建和支架内血栓形成的复合事件。采用多变量调整和逆概率加权来考虑基线差异。多变量调整后,LASM与较大的主要心脏不良事件风险相关(危险比为1.666 [95% CI, 1.041-2.665];P=0.0333)和极晚期支架血栓形成(风险比,3.529 [95% CI, 1.153-10.798];P=0.0271),第一代药物洗脱支架组患者比非lasm组明显增高,而裸金属支架组的差异不明显。反概率加权后结果一致。在第一代药物洗脱支架LASM患者中,继续接受双重抗血小板治疗的患者未发生晚期支架血栓形成。结论LASM与主要心脏不良事件的关系可能与长期随访中植入支架的类型有关,突出了聚合物和药物在药物洗脱支架系统中的临床意义。
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引用次数: 5
Letter by Agbani et al Regarding Article, "Clot Contraction Drives the Translocation of Procoagulant Platelets to Thrombus Surface". Agbani等人关于文章“凝块收缩驱动促凝血小板向血栓表面移位”的来信。
Pub Date : 2019-11-26 DOI: 10.1161/ATVBAHA.119.313468
E. Agbani, I. Hers, A. Poole
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引用次数: 2
Sex Differences in Genomic Drivers of Adipose Distribution and Related Cardiometabolic Disorders: Opportunities for Precision Medicine. 脂肪分布和相关心脏代谢疾病的基因组驱动因素的性别差异:精准医学的机会。
Pub Date : 2019-11-21 DOI: 10.1161/ATVBAHA.119.313154
H. Lumish, M. O'Reilly, M. Reilly
This review focuses on the human genetics, epidemiology, and molecular pathophysiology of sex differences in central obesity, adipose distribution, and related cardiometabolic disorders. Distribution of fat is important for cardiometabolic health, with peripheral fat depots having a protective effect and central visceral fat depots conferring a detrimental effect on health. There are important sex differences in fat distribution that are masked when studying body mass index as a measure of obesity. From epidemiological, murine, and in vitro studies, several mechanisms have been proposed to explain the sex differences in adipose distribution, including sex hormonal effects, cell-intrinsic properties, and the microenvironment in fat depots. More recently, human genetics have revealed hundreds of loci for central obesity providing disruptive opportunities for mechanistic discoveries and clinical translation. A striking feature is that over one-third of these loci have reproducible but poorly understood sexual dimorphic associations with central obesity, most having stronger effects in women. Understanding the genetic and molecular mechanisms of adipose distribution and its sexual dimorphism in humans provides a unique opportunity to advance mechanism-based, sex and gender aware, precision medicine for early identification of at-risk individuals, as well as novel therapeutic strategies for central obesity and cardiometabolic disorders.
本文综述了人类遗传学、流行病学和中枢性肥胖、脂肪分布和相关心脏代谢疾病的性别差异的分子病理生理学。脂肪的分布对心脏代谢健康很重要,外周脂肪库具有保护作用,而中央内脏脂肪库对健康有不利影响。在研究体重指数作为肥胖的衡量标准时,脂肪分布的重要性别差异被掩盖了。从流行病学、小鼠和体外研究中,已经提出了几种机制来解释脂肪分布的性别差异,包括性激素效应、细胞内在特性和脂肪库的微环境。最近,人类遗传学揭示了数百个中心性肥胖的基因座,为机制发现和临床转化提供了破坏性的机会。一个显著的特征是,超过三分之一的这些基因座与中心性肥胖具有可重复的但鲜为人知的两性二态关联,其中大多数对女性有更强的影响。了解人类脂肪分布及其性别二态性的遗传和分子机制,为推进基于机制的、性别和性别意识的精准医学提供了一个独特的机会,可以早期识别高危个体,以及为中枢性肥胖和心脏代谢疾病提供新的治疗策略。
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引用次数: 39
S-Nitrosylation of Plastin-3 Exacerbates Thoracic Aortic Dissection Formation via Endothelial Barrier Dysfunction. s -亚硝基化通过内皮屏障功能障碍加剧胸主动脉夹层形成。
Pub Date : 2019-11-07 DOI: 10.1161/ATVBAHA.119.313440
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
OBJECTIVEThoracic aortic dissection (TAD) is a fatal disease that leads to aortic rupture and sudden death. However, little is known about the effect and molecular mechanism of S-nitrosylation (SNO) modifications in TAD formation. Approach and Results: SNO levels were higher in aortic tissues from TAD patients than in those from healthy controls, and PLS3 (plastin-3) SNO was identified by liquid chromatography-tandem mass spectrometry analysis. Furthermore, tail vein administration of endothelial-specific adeno-associated viruses of mutant PLS3-C566A (denitrosylated form) suppressed the development of TAD in mice, but the wild-type PLS3 (S-nitrosylated form) virus did not. Mechanistically, Ang II (angiotensin II)-induced PLS3 SNO enhanced the association of PLS3 with both plectin and cofilin via an iNOS (inducible nitric oxide synthase)-dependent pathway in endothelial cells. The formation of PLS3/plectin/cofilin complex promoted cell migration and tube formation but weakened adherens junction formation in Ang II-treated endothelial cells. Interestingly, denitrosylated form of PLS3 partially mitigated Ang II-induced PLS3/plectin/cofilin complex formation and cell junction disruption. Additionally, the inhibition of iNOS attenuated PLS3 SNO and the association of PLS3 with plectin and cofilin, thereby modulating endothelial barrier function.CONCLUSIONSOur data indicate that protein SNO modification in endothelial cells modulates the progression of aortic aneurysm and dissection. The iNOS-mediated SNO of PLS3 at the Cys566 site promoted its interaction with cofilin and plectin, thus contributing to endothelial barrier disruption and pathological angiogenesis in TAD.
目的胸主动脉夹层(TAD)是一种导致主动脉破裂和猝死的致命疾病。然而,对s -亚硝基化修饰在TAD形成中的作用和分子机制知之甚少。方法与结果:TAD患者主动脉组织中SNO水平高于健康对照组,并通过液相色谱-串联质谱分析鉴定出PLS3 (plastin-3) SNO。此外,通过尾静脉注射突变体PLS3- c566a的内皮特异性腺相关病毒(脱硝基化形式)可抑制小鼠体内TAD的发育,而野生型PLS3 (s -亚硝基化形式)病毒则无此作用。在机制上,血管紧张素诱导的PLS3通过内皮细胞中iNOS(诱导型一氧化氮合酶)依赖性途径增强了PLS3与plectin和cofilin的关联。在angii处理的内皮细胞中,PLS3/plectin/cofilin复合物的形成促进了细胞迁移和管的形成,但削弱了粘附连接的形成。有趣的是,脱硝基化形式的PLS3部分减轻了Ang ii诱导的PLS3/plectin/cofilin复合物的形成和细胞连接的破坏。此外,iNOS的抑制减弱了PLS3的SNO以及PLS3与plectin和cofilin的关联,从而调节了内皮屏障功能。结论内皮细胞中SNO蛋白的修饰可调节动脉瘤和夹层的进展。inos介导的PLS3在Cys566位点的SNO促进了其与cofilin和plectin的相互作用,从而促进了TAD内皮屏障的破坏和病理性血管生成。
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引用次数: 39
Correction to: Adenosine Monophosphate-Activated Protein Kinase-α2 Deficiency Promotes Vascular Smooth Muscle Cell Migration via S-Phase Kinase-Associated Protein 2 Upregulation and E-Cadherin Downregulation. 更正:单磷酸腺苷活化蛋白激酶-α2缺乏通过s期激酶相关蛋白2上调和e-钙粘蛋白下调促进血管平滑肌细胞迁移。
Pub Date : 2019-11-01 DOI: 10.1161/atv.0000000000000088
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引用次数: 1
Functional Characterization of LIPA (Lysosomal Acid Lipase) Variants Associated With Coronary Artery Disease. 与冠状动脉疾病相关的LIPA(溶酶体酸性脂肪酶)变异的功能特征
Pub Date : 2019-10-24 DOI: 10.1161/ATVBAHA.119.313443
T. Evans, Xiangyu Zhang, Reece E Clark, A. Alisio, Eric Song, Hanrui Zhang, M. Reilly, N. Stitziel, B. Razani
OBJECTIVELIPA (lysosomal acid lipase) mediates cholesteryl ester hydrolysis, and patients with rare loss-of-function mutations develop hypercholesterolemia and severe disease. Genome-wide association studies of coronary artery disease have identified several tightly linked, common intronic risk variants in LIPA which unexpectedly associate with increased mRNA expression. However, an exonic variant (rs1051338 resulting in T16P) in linkage with intronic variants lies in the signal peptide region and putatively disrupts trafficking. We sought to functionally investigate the net impact of this locus on LIPA and whether rs1051338 could disrupt LIPA processing and function to explain coronary artery disease risk. Approach and Results: In monocytes isolated from a large cohort of healthy individuals, we demonstrate both exonic and intronic risk variants are associated with increased LIPA enzyme activity coincident with the increased transcript levels. To functionally isolate the impact of rs1051338, we studied several in vitro overexpression systems and consistently observed no differences in LIPA expression, processing, activity, or secretion. Further, we characterized a second common exonic coding variant (rs1051339), which is predicted to alter LIPA signal peptide cleavage similarly to rs1051338, yet is not linked to intronic variants. rs1051339 also does not impact LIPA function in vitro and confers no coronary artery disease risk.CONCLUSIONSOur findings show that common LIPA exonic variants in the signal peptide are of minimal functional significance and suggest coronary artery disease risk is instead associated with increased LIPA function linked to intronic variants. Understanding the mechanisms and cell-specific contexts of LIPA function in the plaque is necessary to understand its association with cardiovascular risk.
目的:溶酶体酸性脂肪酶(lysosomal acid lipase,简称ipa)介导胆固醇酯水解,具有罕见功能缺失突变的患者可发生高胆固醇血症和严重疾病。冠状动脉疾病的全基因组关联研究已经确定了LIPA中几个紧密相关的常见内含子风险变异,这些变异出乎意料地与mRNA表达增加相关。然而,外显子变异(rs1051338导致T16P)与内含子变异连锁,位于信号肽区,据推测会破坏运输。我们试图从功能上研究该基因座对LIPA的净影响,以及rs1051338是否可以破坏LIPA的加工和功能,从而解释冠状动脉疾病的风险。方法和结果:在从一大群健康个体中分离的单核细胞中,我们证明了外显子和内含子风险变异与LIPA酶活性升高相关,同时转录物水平升高。为了从功能上分离rs1051338的影响,我们研究了几种体外过表达系统,一致地观察到LIPA的表达、加工、活性或分泌没有差异。此外,我们还鉴定了第二种常见的外显子编码变异(rs1051339),该变异与rs1051338类似,预计会改变LIPA信号肽的切割,但与内含子变异无关。rs1051339也不影响体外LIPA功能,没有冠状动脉疾病风险。结论我们的研究结果表明,信号肽中常见的LIPA外显子变异的功能意义很小,提示冠状动脉疾病的风险与与内含子变异相关的LIPA功能增加有关。了解斑块中LIPA功能的机制和细胞特异性背景对于了解其与心血管风险的关联是必要的。
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引用次数: 13
Tapping Into the Strengths of Diversity Among Atherosclerotic Pigs. 挖掘动脉粥样硬化猪多样性的优势。
Pub Date : 2019-10-23 DOI: 10.1161/ATVBAHA.119.313404
J. Bentzon
Arterioscler Thromb Vasc Biol. 2019;39:2203–2204. DOI: 10.1161/ATVBAHA.119.313404 November 2019 2203 Correspondence to: Jacob F. Bentzon, MD, PhD, Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III (FSP), C/Melchor Fernández Almagro 3, 28029 Madrid, Spain. Email jfbentzon@cnic.es For Sources of Funding and Disclosures, see page 2204. © 2019 American Heart Association, Inc. EDITORIAL
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引用次数: 0
Y-Chromosome Genetic Variation Associated With Atherosclerosis and Inflammation. 与动脉粥样硬化和炎症相关的y染色体遗传变异。
Pub Date : 2019-10-23 DOI: 10.1161/ATVBAHA.119.313369
A. Lusis
Human GWAS (Genome-Wide Association Studies) have identified over 100 loci contributing to coronary artery disease (CAD), but such studies have largely ignored the Y chromosome (chr).1 In this issue of ATVB, Eales et al2 have identified a significant association between genetic variants on the Y chr and CAD in 129 133 men from the UK Biobank study. They followed up on this finding by identifying epigenetic and gene expression patterns associated with the variants and they present evidence that the Y chr gene ubiquitously transcribed tetratricopeptide repeat-containing Y-linked, a histone demethylase, may contribute through its inflammatory effects in macrophages.
人类全基因组关联研究(GWAS)已经确定了100多个与冠状动脉疾病(CAD)有关的位点,但这些研究在很大程度上忽略了Y染色体(chr)在本期《ATVB》中,Eales等人在英国生物银行研究的1229133名男性中发现了Y染色体遗传变异与CAD之间的显著关联。他们通过识别与变异相关的表观遗传和基因表达模式对这一发现进行了追踪,并提出证据表明,Y chr基因无处不在地转录含有四肽重复序列的Y-linked,一种组蛋白去甲基化酶,可能通过其在巨噬细胞中的炎症作用发挥作用。
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引用次数: 3
期刊
Arteriosclerosis, Thrombosis, & Vascular Biology
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