Role of CCN5 in heart failure related arrhythmias

项目摘要 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，易患 心源性猝死。纤维化是这些患者的一个显著特征，它对 心律失常。现有的对抗心力衰竭患者心律失常的治疗方法在以下方面存在不足 这在很大程度上是因为它们未能逆转先前存在的纤维化。基质细胞蛋白CCN5介导疾病 通过诱导适应性心脏反应来对抗压力超负荷诱导的应激反应。而当 内源性CCN5具有很强的抗纤维化作用，我们发现慢性AAV9介导的过度表达 CCN5在晚期心力衰竭后负荷增加(HF/ial)模型中的作用 衰老和/或高血压未能恢复传导或预防心律失常。此外，我们初步的 数据表明，AAV9介导的CCN5 OE导致先于 慢性压力超负荷模型中的结构重构。最后，我们发现AAV9介导的CCN5 在结构正常(无纤维化)的心脏中，OE导致传导显著减慢，而 膜兴奋性提示CCN5对细胞间偶联的抑制作用 这可能会干扰其在治疗晚期心力衰竭方面的有益效果。我们的中心假设是 通过CCN5抑制纤维化的潜在抗心律失常效果受到有害因素的阻碍 (非纤维化)电生理效应。我们目前的研究是为定义纤维化而定制的- CCN5的依赖和独立特性，并以治疗的方式利用这一知识。我们的目标是 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，而不是慢性全球 转导。总体而言，该项目的完成将使人们更好地理解纤维化在 心律失常的发生和指导基于机制的抗心律失常方法的发展 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 进一步建立一种在健康和疾病中调节细胞间耦合的新机制。研究项目： 这项高风险的R21提案解决了目前阻碍潜在有效抗纤维化的关键障碍 从前进的治疗。

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.