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： 病理性心脏肥大（PCH）是致命性室性心律失常的独立危险因素 在 PKA 期间，对于预防或治疗 PCH 的更有效疗法的临床需求尚未得到满足。 交感神经/β-肾上腺素能系统刺激后的激活对于心率的正常调节至关重要 和心肌收缩力，交感神经/β-肾上腺素能系统/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，但这种情况仍然存在。 目前尚不清楚 PKA 如何促进 PCH，以及操纵 PKA 激活是否可用于治疗或预防 PCH。 我们发现，PKA 活性受到心脏内源性 PKA 抑制肽 (PKI) 的负调节。 首次将 PKI 亚型之一 PKIα 集中在成人心肌细胞的细胞核中并保持 核 PKA 激活对刺激不太敏感，并且激活速度比胞质 PKA 慢。 此外，压力超负荷会降低 PKIα 的表达，尤其是在细胞核中，及其抑制 PKIα 的能力。 当 PKIα 在小鼠体内被基因消除时，核 PKA 活性增强，导致 PKIα 活性意外降低。 另一方面，当压力超负荷后PCH仅受到PKA抑制时。 PKIα (PKAi) 的结构域，压力超负荷引起的 PCH 减弱。我们的培养肌细胞研究表明。 PCH 的减少与胞质 PKA 抑制有关，因此，我们提出 PKA 的定位。 激活对于 PCH 的发育至关重要，具体取决于细胞位置（隔室）。 PKA 激活过程中，PKA 可以促进或减弱压力过载引起的 PCH。 基于这些初步研究，我们发现：虽然胞质 PKA 激活是促肥大的， 核 PKA 激活具有抗肥厚作用；内源性 PKIα 对核 PKA 激活具有抑制作用。 进一步预测，通过增强核 PKA 来抑制胞质 PKA 将是预防或预防的理想策略。 我们将在三个目标上检验这一假设：1）确定基因剂量依赖性效应和 整体心肌细胞特异性 PKA 抑制（PKAi）对心脏结构和功能的机制 响应肥大应激的重塑 2) 确定抑制胞质 PKA 的效果（使用 a 胞浆靶向 PKAi) 对 PCH 发育的影响 3) 确定 PKIα 激活核 PKA 的影响。 敲除或核 PKA 过度表达或核 PKA 抑制对 PCH 发展的影响。 拟议研究的完成将为隔室 PKA 的作用提供新的见解 以及 PKIα 在 PCH 开发中的监管将揭示该项目产生的新知识。 开发预防和治疗患者 PCH 的新治疗策略。