RECK in Adverse Cardiac Remodeling and Heart Failure

RECK 在不良心脏重构和心力衰竭中的应用

• 批准号: 10368301
• 负责人: Chandrasekar Bysani
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10368301
• 关键词: Age-Years; Angiotensin II; Angiotensins; Aortic Valve Stenosis; Biochemical; Cardiac; Cardiac Myocytes; Caring; Cessation of life; Characteristics; Chronic; Complex; Congestive Heart Failure; Coupled; Data; Dependovirus; Development; Disease; Disintegrins; Epidermal Growth Factor Receptor; Fibroblasts; Fibrosis; Functional disorder; GPI Membrane Anchors; Gene Deletion; Genetic; Goals; Healthcare Systems; Heart; Heart Hypertrophy; Heart failure; Histologic; Hospitalization; Human; Hypertension; Hypertrophy; IL6ST gene; In Vitro; Inflammation Mediators; Infusion procedures; Intervention; Left Ventricular Hypertrophy; Matrix Metalloproteinases; Mediator of activation protein; Medicare; Membrane; Metalloproteases; Molecular; Morbidity - disease rate; Mus; Myocardial; Pathogenesis; Patients; Pharmacological Treatment; Pharmacology; Play; Prevention; Prevention strategy; Process; Profibrotic signal; Proteins; Public Health; Publishing; Reporting; Repression; Role; Secondary to; Serotyping; Signal Transduction; Structure; Testing; Transgenic Organisms; United States Department of Veterans Affairs; Veterans; Wild Type Mouse; base; cardiac magnetic resonance imaging; cardioprotection; constriction; coronary fibrosis; cost; cysteine rich protein; experience; glycoprotein 130; hemodynamics; hospital readmission; improved; improved outcome; in vivo; lifetime risk; migration; mortality; new therapeutic target; novel; novel therapeutic intervention; older patient; overexpression; pressure; prevent; promoter; protective effect; therapeutic gene; treatment strategy

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.

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医院再入院和死亡的主要原因之一。实际上， 40岁以上的HF终身风险为5分。 在医疗保险和退伍军人中，有20％以上的患者中有20％的出院。这些医疗保健在一起 系统为HF护理产生了近372亿美元。大量患者出现严重的左 继发压力超负荷（例如高血压，主动脉瓣狭窄）的心室肥大（LVH）和 经历情节性的严重充血HF，住院和死亡率增加。 HF的机制很复杂，包括局部和系统的神经激素变化以及 血液动力学超负荷。 RECK（诱导与Kazal图案的富含半胱氨酸蛋白质富含半胱氨酸的蛋白质）是独特的 膜锚定的蛋白质抑制许多负责心脏重塑的介质， 包括MMP（基质金属蛋白酶），ADAMS（崩解蛋白和金属蛋白酶），EGFR和EGFR和 炎症介体。我们发表的报告表明，血管紧张素（ANG）-II，一个关键的调解人 高血压引起的不良心脏重塑，抑制了体内RECK。而且，Ang-II被抑制 RECK和诱导MMP激活和心脏成纤维细胞在体外迁移，其作用被逆转 Reck的异位过表达。我们的初步数据表明，横向主动脉的压力超负荷（PO） 收缩（TAC）抑制了RECK并增加了野生型小鼠心脏中的MMP激活。而老鼠 诱导型心肌细胞特异性的RECK基因缺失自发发展心脏肥大和 纤维化，这些作用被TAC PO加剧了。相比之下，特定于心肌细胞特定的RECK 过表达抑制了PO诱导的肥大，纤维化和收缩功能障碍。重要的是，Reck 肥厚的（主动脉狭窄）和非缺血性人类心脏失败的表达均降低。 基于这些关键和新颖的初步数据，我们的中心假设是逆转 抑制或增强其在心脏中的表达将钝化引起的不良结构重塑和 通过靶向促肌营养性和促纤维化介体来进展到HF。我们的长期目标是 了解心肌肥大的病理生理学的分子机制及其 过渡到HF，并确定用于干预和治疗的新型治疗靶标。我们的直接 目标是更好地表征Reck在抑制PO诱导的发病机理中的心脏保护作用 不良心脏重塑和HF开发，并制定一种介绍其介绍的策略 心脏表达。为了检验我们的中心假设，提出了三个具体目标： 在AIM 1中，我们将（a）阐明RECK缺失在有条件的心肌细胞特异性方面的影响 心肌肥大，纤维化和功能障碍的自发发展的方式，（b）确定 Reck删除是否会加剧对不良重塑的影响。在AIM 2中，我们将确定是否 诱导型心肌细胞特异性划线过表达将阻止建立或反向建立 PO引起的不良心脏重塑和功能障碍，并发展为HF。在AIM 3中，我们将确定 使用基于AAV9的基因治疗方法对RECK的异位过表达是否会阻止 开发或反向建立的PO引起的不良心脏重塑和HF。 因此，我们提出的遗传和基因治疗方法将（i）描述基本 RECK在心脏结构和功能中的作用，（ii）将其作为关键抗嗜肺的作用表征 PO中的抗纤维化介体，（iii）证明了它在心脏中的诱导是一种新颖 不良结构和功能重塑对心脏的钝性进展的治疗方法 失败。