RECK in Adverse Cardiac Remodeling and Heart Failure

根据美国退伍军人事务部，心力衰竭（HF）和相关并发症 是退伍军人医疗保健系统中再次入院和死亡的主要原因之一。事实上， 在40岁以上，发生HF的终生风险为1/5。HF再入院发生在30天内 在医疗保险和退伍军人中，20%的65岁以上的患者出院。这些医疗保健 系统花费了近372亿美元用于HF护理。大量患者出现严重的左 继发于压力超负荷的心室肥大（LVH）（例如，高血压、主动脉瓣狭窄），以及 出现偶发性重度充血性HF、住院和死亡率增加。 HF的机制很复杂，包括局部和全身神经激素变化， 血流动力学过载。RECK（Reversion Inducing Cysteine Rich Protein with Kazal motifs）是一种独特的 一种膜锚定蛋白，可抑制许多导致不良心脏重塑的介质， 包括MMP（基质金属蛋白酶）、亚当斯（去整合素和金属蛋白酶）、EGFR和 炎症介质。我们发表的报告表明，血管紧张素（Ang）-II，一个关键的调解人， 高血压诱导的不良心脏重塑，抑制体内RECK。此外，Ang-II抑制了 RECK和诱导的MMP激活和心脏成纤维细胞迁移，这种作用被逆转， RECK的异位过表达。我们的初步数据表明，横向主动脉压力超负荷（PO） 收缩（TAC）抑制RECK并增加野生型小鼠心脏中的MMP活化。而老鼠 具有可诱导的心肌细胞特异性RECK基因缺失的患者自发地发展为心脏肥大， 纤维化，并且这些作用通过TAC的PO而加剧。相反，心肌细胞特异性RECK 过表达抑制PO诱导的肥大、纤维化和收缩功能障碍。重要的是，雷克 在肥大（主动脉瓣狭窄）和非缺血性起源的衰竭的人心脏中表达都降低。 基于这些关键和新颖的初步数据，我们的中心假设是，逆转RECK 抑制或增强其在心脏中的表达将减弱PO诱导的不良结构重塑， 通过靶向促肥大和促纤维化介质进展为HF。我们的长期目标是 了解心肌肥大及其病理生理学的分子机制， 过渡到HF，并确定用于干预和治疗的新的治疗靶点。我们眼前的 目的是更好地表征RECK在抑制PO诱导的心肌损伤发病机制中的心脏保护作用。 不利的心脏重塑和HF发展，并制定干预策略，以诱导其 在心中的表达。为了检验我们的中心假设，提出了三个具体目标： 在目标1中，我们将（a）阐明RECK缺失对条件性心肌细胞特异性 方法，以及（B）确定 RECK缺失是否加重PO诱导的不良重塑。在目标2中，我们将确定 可诱导的心肌细胞特异性RECK过表达将阻止或逆转已建立的 PO诱导的不良心脏重塑和功能障碍以及进展为HF。在目标3中，我们将确定 使用基于AAV 9的基因治疗方法的RECK的异位过表达是否会阻止 发展或逆转已建立的PO诱导的不良心脏重塑和HF。 因此，我们提出的遗传和基因治疗方法将（i）描绘基本的 RECK在心脏结构和功能中的作用，（ii）表征其作为关键的抗肥大 和抗纤维化介质PO，和（iii）证明其在心脏中的诱导是一种新的 减缓心脏不良结构和功能重塑进展的治疗方法 失败

According to the US Department of Veterans Affairs, heart failure (HF) and associated complications are one of the main reasons for hospital readmissions and death in the Veterans Healthcare System. In fact, above 40 years of age, the lifetime risk of developing HF is 1 in 5. Readmissions for HF occur within 30 days of discharge in 20% of patients older than 65 in the Medicare and Veterans. Together, these healthcare systems incurred nearly $37.2 billion for HF care. A substantial number of patients develop severe left ventricular hypertrophy (LVH) secondary to pressure overload (e.g., hypertension, aortic valve stenosis), and experience episodic severe congestive HF, hospitalization, and increased mortality. The mechanisms of HF are complex and include local and systemic neurohormonal changes and hemodynamic overload. RECK (Reversion Inducing Cysteine Rich Protein with Kazal motifs) is a unique membrane-anchored protein that inhibits many of the mediators responsible for adverse cardiac remodeling, including MMPs (matrix metalloproteinases), ADAMs (A Disintegrin and Metalloproteinase), EGFR, and inflammatory mediators. Our published reports demonstrated that angiotensin (Ang)-II, a critical mediator of hypertension-induced adverse cardiac remodeling, suppresses RECK in vivo. Moreover, Ang-II suppressed RECK and induced MMP activation and cardiac fibroblast migration in vitro, effects that were reversed by the ectopic overexpression of RECK. Our preliminary data show that pressure overload (PO) by transverse aortic constriction (TAC) suppresses RECK and increases MMP activation in a wild type mouse heart. While mice with inducible cardiomyocyte-specific RECK gene deletion spontaneously develop cardiac hypertrophy and fibrosis, and these effects are exacerbated by PO by TAC. In contrast, cardiomyocyte-specific RECK overexpression inhibits PO-induced hypertrophy, fibrosis and contractile dysfunction. Importantly, RECK expression is reduced in both hypertrophied (aortic stenosis) and failing human hearts of non-ischemic origin. Based on these critical and novel preliminary data, our central hypothesis is that reversing RECK suppression or enhancing its expression in the heart will blunt PO-induced adverse structural remodeling and progression to HF by targeting pro-hypertrophic and pro-fibrotic mediators. Our long-term goals are to understand the molecular mechanisms underlying the pathophysiology of myocardial hypertrophy and its transition to HF, and to identify novel therapeutic target(s) for intervention and treatment. Our immediate goals are to better characterize the cardioprotective role of RECK in inhibiting the pathogenesis of PO-induced adverse cardiac remodeling and HF development, and to develop an interventional strategy to induce its expression in the heart. To test our central hypothesis, three specific aims are proposed: In Aim 1, we will (a) Elucidate the impact of RECK deletion in a conditional cardiomyocyte-specific manner on spontaneous development of myocardial hypertrophy, fibrosis and dysfunction, and (b) determine whether RECK deletion exacerbates PO-induced adverse remodeling. In Aim 2, we will determine whether inducible cardiomyocyte-specific RECK overexpression will prevent the development of or reverse established PO-induced adverse cardiac remodeling and dysfunction, and progression to HF. In Aim 3, we will determine whether ectopic overexpression of RECK using an AAV9-based gene therapeutic approach will prevent the development of or reverse established PO-induced adverse cardiac remodeling and HF. Thus, our proposed genetic and gene therapeutic approaches will (i) delineate the fundamental role of RECK in cardiac structure and function, (ii) characterize its role as a critical anti-hypertrophic and anti-fibrotic mediator in PO, and (iii) demonstrate that its induction in the heart is a novel therapeutic approach to blunt progression of adverse structural and functional remodeling to heart failure.