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.

项目摘要 老年人和/或高血压患者的心力衰竭是一种主要的公共卫生流行病，容易患 突然心脏死亡。纤维化是这些患者的标志性特征，对 心律失常。现有用于打击心力衰竭患者心律不齐的疗法不足 大部分是因为它们无法逆转纤维化。母细胞蛋白CCN5介导疾病 通过引起针对压力超负荷引起的应激的自适应心脏反应的回归。尽管 内源性CCN5发挥了有效的抗纤维化功效，我们发现慢性AAV9介导的过表达 CCN5的（OE）在高级心力衰竭的模型中，增加后负载（HF/IAL）模仿的影响 衰老和/或高血压无法恢复传导或预防心律不齐。此外，我们的初步 数据表明，AAV9介导的CCN5 OE会导致不良电重塑之前 在慢性压力超负荷模型中进行结构重塑。最后，我们发现AAV9介导的CCN5 在结构正常（无纤维化）心脏中的OE导致明显的传导减速，而没有变化 膜兴奋性表明，迄今未识别CCN5对细胞间耦合的抑制作用 这可能会干扰其在晚期心力衰竭的情况下其有益的功效。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了有害 （纤维化独立的）电生理作用。我们目前的研究是针对定义纤维化 - CCN5的依赖和独立特性，并以治疗性利用这一知识。我们的目标 保留有益的有益，并避免CCN5通过快速，局部和 使用化学修饰的RNA基因递送方法的瞬时递送，而不是慢性全局 转导。总体而言，该项目的完成将提高人们对纤维化作用的了解 心律失常，并指导基于机制的方法打击心律不齐的方法 患有晚期心力衰竭的患者治疗方法非常有限。这些研究可能 进一步建立了一种新的机制，通过该机制在健康和疾病中受到细胞间耦合的调节。研究 这个高风险的R21提案解决了关键障碍，该障碍目前阻碍了潜在的抗纤维化 前进的治疗。

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