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

基本信息

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
项目类别：
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

项目摘要

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.

据美国退伍军人事务部称，心力衰竭 (HF) 和相关并发症是退伍军人医疗系统中再次入院和死亡的主要原因之一。实际上， 40 岁以上，终生发生心力衰竭的风险为五分之一。心力衰竭在 30 天内再次入院医疗保险和退伍军人医疗保险中 65 岁以上患者的 20% 出院。这些医疗保健共同系统用于心力衰竭护理的费用接近 372 亿美元。相当多的患者出现严重左继发于压力超负荷（例如高血压、主动脉瓣狭窄）的心室肥厚 (LVH)，以及经历阵发性严重充血性心力衰竭、住院治疗和死亡率增加。心力衰竭的机制很复杂，包括局部和全身神经激素的变化和血流动力学超负荷。 RECK（具有 Kazal 基序的逆转诱导富含半胱氨酸蛋白）是一种独特的膜锚定蛋白，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）、ADAM（解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 是高血压引起的不良心脏重塑，抑制体内 RECK。此外，Ang-II 抑制 RECK 并在体外诱导 MMP 激活和心脏成纤维细胞迁移，这些效应可被 RECK 的异位过度表达。我们的初步数据表明，横主动脉压力超负荷（PO）在野生型小鼠心脏中，收缩 (TAC) 抑制 RECK 并增加 MMP 激活。而老鼠诱导性心肌细胞特异性 RECK 基因缺失会自发导致心脏肥大 PO 和 TAC 会加剧纤维化。相反，心肌细胞特异性 RECK 过度表达可抑制 PO 诱导的肥大、纤维化和收缩功能障碍。重要的是，RECK 在肥厚（主动脉瓣狭窄）和非缺血性衰竭的人类心脏中表达均减少。基于这些关键且新颖的初步数据，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和通过靶向促肥大和促纤维化介质进展为心力衰竭。我们的长期目标是了解心肌肥厚病理生理学的分子机制及其过渡到心力衰竭，并确定干预和治疗的新治疗靶点。我们的即时目标是更好地表征 RECK 在抑制 PO 诱导的发病机制中的心脏保护作用不良心脏重塑和心力衰竭的发生，并制定介入策略来诱导其发生表达在心里。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的影响心肌肥厚、纤维化和功能障碍自发发展的方式，以及（b）确定 RECK 缺失是否会加剧 PO 诱导的不良重塑。在目标 2 中，我们将确定是否诱导型心肌细胞特异性 RECK 过度表达将阻止其发展或逆转已建立的 PO 诱发不良心脏重塑和功能障碍，并进展为心力衰竭。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度表达 RECK 是否会阻止发生或逆转已确定的 PO 诱导的不良心脏重塑和心力衰竭。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) 描述其作为关键抗肥厚药物的作用和 PO 中的抗纤维化介质，并且 (iii) 证明其在心脏中的诱导是一种新颖的减缓心脏结构和功能重塑不良进展的治疗方法失败。