RECK in Adverse Cardiac Remodeling and Heart Failure

根据美国退伍军人事务部的说法，心力衰竭(HF)及其相关并发症 是退伍军人医疗系统中重新入院和死亡的主要原因之一。事实上, 40岁以上患心力衰竭的终生风险为五分之一。30天内再次入院 在医疗保险和退伍军人中，65岁以上的患者中有20%的人出院。总而言之，这些医疗保健 系统公司在心力衰竭护理上花费了近372亿美元。相当数量的患者发展成严重的左撇子 继发于压力超负荷(如高血压、主动脉瓣狭窄)的左心室肥厚 经历发作性严重充血性心力衰竭、住院和死亡率增加。 心力衰竭的机制是复杂的，包括局部和全身的神经激素变化和 血流动力学过载。RECK是一种独特的具有Kazal基序的逆转诱导富含半胱氨酸的蛋白 膜锚定蛋白能抑制许多导致心脏不良重塑的介质， 包括MMPs(基质金属蛋白酶)、ADAMS(去整合素和金属蛋白酶)、EGFR和 炎症介质。我们已发表的报告表明，血管紧张素-II是血管紧张素转换酶的关键介体。 高血压诱导的不良心脏重塑，在体内抑制RECK。此外，Ang-II还抑制了 RECK和诱导的基质金属蛋白酶的激活和心脏成纤维细胞的迁移，这一作用可被 RECK基因的异位过度表达。我们的初步数据显示，横主动脉的压力超负荷(PO) 收缩(TAC)抑制RECK并增加野生型小鼠心脏中的基质金属蛋白酶活性。而老鼠 具有可诱导的心肌细胞特异性RECK基因缺失的自发性心肌肥厚和 纤维化，而TAC的PO加剧了这些影响。相比之下，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 在肥厚(主动脉狭窄)和衰竭的非缺血来源的人心脏中表达均减少。 基于这些关键的和新颖的初步数据，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钝化PO诱导的不利结构重构和 通过靶向促肥大和促纤维化介质进展为心衰。我们的长期目标是 了解心肌肥厚及其病理生理机制的分子机制 过渡到心衰，并寻找新的治疗靶点(S)进行干预和治疗。我们的直接客户 目的是更好地表征RECK在抑制PO诱导的心肌损伤中的心脏保护作用 不利的心脏重构和心衰的发展，并开发一种干预策略，以诱导其 在心里流露出来。为了验证我们的中心假设，我们提出了三个具体目标： 在目标1中，我们将(A)阐明RECK缺失在条件性心肌细胞特异性中的影响 心肌肥大、纤维化和功能障碍自发发展的方式，以及(B)确定 RECK缺失是否加剧PO诱导的不利重构。在目标2中，我们将确定是否 可诱导的心肌细胞特异性RECK过表达将防止或逆转已建立的 PO诱导的不良心脏重构和功能障碍，并进展为心衰。在目标3中，我们将确定 使用基于AAV9的基因治疗方法异位过表达RECK是否会防止 发展或逆转已建立的PO诱导的不良心脏重塑和心衰。 因此，我们提出的遗传和基因治疗方法将(I)描绘出基本的 RECK在心脏结构和功能中的作用，(Ii)表征其作为一种关键的抗肥厚因子的作用 和PO中的抗纤维化介质，以及(Iii)证明其在心脏中的诱导是一种新的 心脏结构和功能不良重构进展迟缓的治疗方法 失败了。

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.