Role of CCN5 in heart failure related arrhythmias

CCN5 在心力衰竭相关心律失常中的作用

• 批准号: 9315062
• 负责人: FADI GABRIEL AKAR
• 金额: $ 21.19万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315062
• 关键词: Acceleration; Action Potentials; Acute; Address; Affect; Aging; Animals; Arrhythmia; Biological Assay; Cardiac; Cardiac Myocytes; Cells; Chemicals; Chronic; Co-Immunoprecipitations; Coculture Techniques; Complement; Connexins; Coupling; Data; Development; Disease; Disease regression; Echocardiography; Elderly; Electrophysiology (science); Epidemic; Fibrosis; Functional disorder; Future; Gap Junctions; Gene Delivery; Gene Transfer; Health; Heart; Heart failure; Human; Hypertension; In Vitro; Infarction; Injury; Knowledge; Mechanics; Mediating; Membrane; Modeling; Muscle Cells; Myocardial Infarction; Myofibroblast; Nature; Optics; Pathologic; Patients; Phase; Preventive; Property; Proteins; Public Health; RNA; Rattus; Reperfusion Injury; Role; Severities; Stress; Testing; Therapeutic; Therapeutic Intervention; Time; Transforming Growth Factor beta; Western Blotting; age effect; base; combat; high risk; improved; in vivo; monolayer; novel; operation; overexpression; pressure; prevent; protective efficacy; repaired; response; small hairpin RNA; sudden cardiac death

Project Summary Heart failure in elderly and/or hypertensive patients is a major public health epidemic that predisposes to sudden cardiac death. Fibrosis is a hallmark feature of these patients that contributes significantly to arrhythmogenesis. Existing therapies for combatting arrhythmias in heart failure patients are inadequate in large part because they fail to reverse preexisting fibrosis. The matricellular protein CCN5 mediates disease regression by eliciting an adaptive cardiac response against pressure overload induced stress. While endogenous CCN5 exerts a potent anti-fibrosis efficacy, we found that chronic AAV9-mediated overexpression (OE) of CCN5 in models of advanced heart failure with increased afterload (HF/iAL) that mimic the effects of aging and/or hypertension failed to restore conduction or prevent arrhythmias. Furthermore, our preliminary data demonstrate that AAV9-mediated CCN5 OE causes adverse electrical remodeling that precedes structural remodeling in a chronic model of pressure overload. Finally, we found that AAV9-mediated CCN5 OE in structurally normal (fibrosis-free) hearts caused significant conduction slowing with no change in membrane excitability suggesting a hitherto unrecognized inhibitory effect of CCN5 on inter-cellular coupling that may interfere with its beneficial efficacy in the setting of advanced heart failure. Our central hypothesis is that the potential anti-arrhythmic efficacy of suppressing fibrosis through CCN5 is hampered by detrimental (fibrosis-independent) electrophysiological effects. Our current studies are tailored to define the fibrosis- dependent and independent properties of CCN5 and to harness this knowledge therapeutically. We aim to retain the beneficial and avoid the detrimental (fibrosis-independent) effects of CCN5 through rapid, local, and transient delivery using a chemically modified RNA gene delivery approach as opposed to chronic global transduction. Overall, completion of this project will lead to improved understanding of the role of fibrosis in arrhythmogenesis and guide the development of mechanism-based approaches for combatting arrhythmias in patients with advanced heart failure who currently have very limited therapeutic options. These studies may further establish a novel mechanism by which cell-to-cell coupling is regulated in health and disease. Studies in this high-risk R21 proposal address critical barriers that currently obstruct a potentially power anti-fibrosis therapy from advancing forward.

项目概要 老年和/或高血压患者的心力衰竭是一种主要的公共卫生流行病，容易导致 心源性猝死。纤维化是这些患者的一个标志性特征，对 心律失常。现有的治疗心力衰竭患者心律失常的疗法在以下方面是不够的： 很大程度上是因为它们无法逆转先前存在的纤维化。基质细胞蛋白 CCN5 介导疾病 通过引发针对压力超负荷引起的应激的适应性心脏反应来回归。尽管 内源性 CCN5 发挥有效的抗纤维化功效，我们发现 AAV9 介导的慢性过度表达 (OE) CCN5 在后负荷增加 (HF/iAL) 的晚期心力衰竭模型中的作用，模拟 衰老和/或高血压未能恢复传导或预防心律失常。此外，我们初步 数据表明 AAV9 介导的 CCN5 OE 会导致不利的电重塑 压力过载慢性模型中的结构重塑。最后，我们发现AAV9介导的CCN5 结构正常（无纤维化）心脏中的 OE 导致传导显着减慢，但没有变化 膜兴奋性表明 CCN5 对细胞间偶联具有迄今为止未被认识的抑制作用 这可能会干扰其在晚期心力衰竭情况下的有益功效。我们的中心假设是 通过 CCN5 抑制纤维化的潜在抗心律失常功效受到有害物质的阻碍 （与纤维化无关的）电生理效应。我们目前的研究旨在定义纤维化- CCN5 的依赖性和独立特性，并在治疗上利用这些知识。我们的目标是 通过快速、局部和有效的方式保留 CCN5 的有益作用并避免有害（与纤维化无关）的影响 使用化学修饰的 RNA 基因传递方法进行瞬时传递，而不是慢性全局传递 转导。总体而言，该项目的完成将有助于更好地了解纤维化在 心律失常发生并指导开发基于机制的方法来对抗心律失常 目前治疗选择非常有限的晚期心力衰竭患者。这些研究可能 进一步建立了一种在健康和疾病中调节细胞间偶联的新机制。研究于 这项高风险的 R21 提案解决了目前阻碍潜在抗纤维化的关键障碍 治疗从前进。

项目成果

Primary Effect of SERCA 2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction.

SERCA 2a 基因转移对慢性心肌梗死传导储备的主要影响。

• DOI: 10.1161/jaha.118.009598
• 发表时间: 2018
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Motloch,LukasJ;Cacheux,Marine;Ishikawa,Kiyotake;Xie,Chaoqin;Hu,Jun;Aguero,Jaume;Fish,KennethM;Hajjar,RogerJ;Akar,FadiG
• 通讯作者: Akar,FadiG