Compartmental PKA and Pathological Cardiac Hypertrophy

室室 PKA 和病理性心脏肥大

• 批准号: 9595818
• 负责人: Xiongwen Chen
• 金额: $ 39.63万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9595818
• 关键词: Adrenergic Agents; Adult; Agonist; Aortic Valve Stenosis; Arrhythmia; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiovascular Diseases; Catalytic Domain; Cell Nucleus; Cells; Cessation of life; Clinic; Clinical; Complex; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Cytosol; Data; Development; Disease; Dose; Exposure to; Functional disorder; Genes; Goals; Heart; Heart Contractilities; Heart Hypertrophy; Heart Rate; Heart failure; Hypertension; Hypertrophy; Incidence; Interruption; Intervention; Knock-out; Knockout Mice; Knowledge; Light; Location; Mediating; Mental Depression; Modality; Modification; Molecular; Mus; Muscle Cells; Myocardium; Neonatal; Nuclear; Nuclear Protein; PKA inhibitor; Pathologic; Pathologic Processes; Patients; Peptides; Physiological Processes; Play; Prevention strategy; Protein Inhibition; Protein Isoforms; Protein Kinase A Inhibitor; Rattus; Reagent; Regulation; Research; Risk; Risk Factors; Role; Signal Transduction; Stress; Structure; System; Testing; Time; Transgenic Mice; Transgenic Organisms; United States; Ventricular Arrhythmia; Work; base; cardiogenesis; constriction; effective therapy; heart cell; heart function; hemodynamics; improved; insight; muscle form; novel; novel strategies; novel therapeutics; overexpression; premature; pressure; prevent; protein activation; response

Project Summary/Abstract: Pathological cardiac hypertrophy (PCH) is an independent risk factor for lethal ventricular arrhythmias and heart failure. There is an unmet clinical need for more effective therapies to prevent or treat PCH. While PKA activation after sympathetic/β-adrenergic system stimulation is essential for the normal regulation of heart rate and cardiac contractility, persistent activation of sympathetic/β-adrenergic system/protein kinase A (PKA) in cardiovascular diseases such as hypertension leads to PCH and contractile dysfunction. However, it remains unclear how PKA promotes PCH and if manipulating PKA activation can be used to treat or prevent PCH. PKA activity is negatively regulated by endogenous PKA inhibitor peptides (PKI) in the heart. We found for the first time that one of the PKI isoform, PKIα, is concentrated in the nucleus of adult cardiomyocytes and keeps nuclear PKA activation less sensitive to stimulation and activated at a slower rate than cytosolic PKA. Furthermore, pressure overload reduces PKIα expression, especially in the nucleus, and its capability to inhibit PKA. When PKIα is genetically ablated in mice, nuclear PKA activity is enhanced, leading to surprisingly reduced PCH after pressure overload. On the other hand, when myocyte PKA is inhibited by only the PKA inhibition domain of PKIα (PKAi), PCH induced by pressure overload is blunted. Our cultured myocyte study suggest that this PCH reduction is related to cytosolic PKA inhibition. Therefore, we propose that the localization of PKA activation is crucial for its effect on the development of PCH. Depending on the cellular location (compartment) of PKA activation, PKA can either promote or blunt PCH induced by pressure overload. Based on these preliminary studies, we hypothesize that: while cytosolic PKA activation is prohypertrophic, nuclear PKA activation is antihypertrophic; endogenous PKIα exerts inhibition on nuclear PKA activation. We further predict that cytosolic PKA inhibition with enhanced nuclear PKA will be a desired strategy to prevent or treat PCH. We’ll test the hypothesis in three aims: 1) To determine the gene dose-dependent effects and mechanisms of global cardiomyocyte-specific PKA inhibition (PKAi) on cardiac structural and functional remodeling in response to hypertrophic stress. 2) To determine the effects of inhibiting cytosol PKA (with a cytosol-targeted PKAi) on PCH development. 3) To determine the effects of nuclear PKA activation by PKIα knockout or nuclear PKA overexpression or nuclear PKA inhibition on the development of PCH. The accomplishment of the proposed studies will provide novel insights into the roles of compartmental PKA and its regulation by PKIα in the development of PCH. New knowledge generated from this project will shed light into developing novel therapeutic strategy for the prevention and treatment of PCH in patients.

项目摘要/摘要： 病理心脏肥大（PCH）是致命性心律不齐和 心脏衰竭。对预防或治疗PCH的更有效疗法的临床需求未满足。而PKA 交感/β-肾上腺素能系统刺激后的激活对于正常的心率调节至关重要 和心脏收缩力，交感/β-肾上腺素系统/蛋白激酶A（PKA）的持续激活 高血压等心血管疾病会导致PCH和收缩功能障碍。但是，它仍然是 不清楚PKA如何促进PCH以及是否可以使用操纵PKA激活来治疗或预防PCH。 心脏内源性PKA抑制剂肽（PKI）对PKA活性负调节。我们找到了 PKI同工型PKIα首次集中在成年心肌细胞的核中，并保持 核PKA激活对刺激的敏感性不太敏感，并且比胞质PKA较慢。 此外，压力超负荷降低了PKIα表达，尤其是在核中，其能力抑制 PKA。当PKIα在小鼠中遗传消融时，核PKA活性会增强，导致出人意料地降低 压力超负荷后PCH。另一方面，仅PKA抑制抑制Myocyte PKA 由压力超负荷诱导的PCH的PCH（PKAI）域被钝化。我们培养的肌细胞研究表明 该PCH还原与胞质PKA抑制有关。因此，我们建议PKA的定位 激活对于它对PCH发展的影响至关重要。取决于蜂窝位置（车厢） 在PKA激活中，PKA可以促进或钝性PCH，由压力超负荷引起。 基于这些初步研究，我们假设：胞质PKA激活是亲身性的，但 核PKA激活是抗肿瘤的；内源性PKIα对核PKA激活施加抑制作用。我们 进一步预测，用增强核PKA抑制胞质PKA将是预防或 治疗PCH。我们将以三个目的测试假设：1）确定基因剂量依赖性效应和 全球心肌细胞特异性PKA抑制（PKAI）对心脏结构和功能的机制 响应肥厚应激的重塑。 2）确定抑制细胞质PKA的影响（用A PCH开发的细胞质靶向PKAI）。 3）确定PKIα核PKA激活的影响 敲除或核PKA过表达或核PKA抑制PCH的发展。 拟议研究的成就将提供对隔室PKA作用的新见解 PKIα在PCH的发展中对其进行调节。该项目产生的新知识将浮出水面 制定用于预防和治疗患者PCH的新型治疗策略。