RGS Protein Function in Cardiac Physiology

RGS 蛋白在心脏生理学中的功能

• 批准号: 6917674
• 负责人: ANTHONY JUSTIN MUSLIN
• 金额: $ 34.43万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917674
• 关键词: biological signal transduction; blood pressure; cardiac myocytes; cardiovascular disorder epidemiology; cell growth regulation; disease /disorder model; exercise; gene deletion mutation; gene expression; gene targeting; genetically modified animals; guanosinetriphosphatase activating protein; heart contraction; heart disorder; heart function; laboratory mouse; laboratory rat; newborn animals; pathologic process; protein structure function; tissue /cell culture; ventricular hypertrophy

DESCRIPTION (provided by applicant): Cardiac hypertrophy in humans is frequently associated with a poor prognosis. In cultured rat cardiac myocytes, ligands such as phenylephrine, endothelin-1, angiotensin II, and prostaglandin F2alpha promote a hypertrophic response. There is evidence that the action of these ligands on cultured cells mimics cardiac hypertrophy in humans. Most agonists that cause cultured cardiomyocytes to hypertrophy signal via heterotrimeric G proteins. Regulator of G protein signaling (RGS) proteins are GTPase activating proteins (GAPs) that deactivate asubunits of heterotrimeric G proteins. The main aim of this proposal is to investigate the physiologic role of RGS proteins in the regulation of cardiac hypertrophic growth program. The central hypothesis is that RGS proteins determine the responsiveness of cardiac myocytes to extracellular stimuli, and that RGS gene expression is increased as an adaptive mechanism to limit Gprotein- mediated signal transduction. In the original funding period, we demonstrated that RGS proteins are present in heart, that RGS3 and RGS4 gene expression is responsive to external stimuli, that cardiacspecific overexpression of RGS4 in mice blocks pressure overload- and exercise-induced cardiac hypertrophy, and that RGS4 is a GAP for Gq in the in vivo heart. Despite these findings, many questions remain about the role of RGS proteins in heart disease. In the next phase of this project, we propose to investigate the specific role of RGS2, RGS3, and RGS4, in cardiac myocyte hypertrophy by use of a "knock-down" strategy in cultured cells. Second, we investigate the specific role of RGS4 in pressure overload- and exercise-induced cardiac hypertrophy by use of mice with both whole-body and cardiacspecific targeted disruption of this gene. Third, we investigate the specific role of RGS3 in pressure overload- and exercise-induced cardiac hypertrophy by use of mice with whole-body targeted disruption of this gene. These experiments will help define the role of RGS proteins in the pathogenesis of cardiac hypertrophy and contractile dysfunction and may provide important information for the development of novel therapeutic agents.

描述（由申请人提供）：人类心脏肥大常常与不良预后相关。在培养的大鼠心肌细胞中，去氧肾上腺素、内皮素-1、血管紧张素 II 和前列腺素 F2α 等配体可促进肥大反应。有证据表明这些配体对培养细胞的作用模拟了人类的心脏肥大。大多数激动剂通过异三聚体 G 蛋白引起培养的心肌细胞肥大信号。 G 蛋白信号传导 (RGS) 蛋白的调节蛋白是 GTP 酶激活蛋白 (GAP)，可以使异源三聚体 G 蛋白的亚基失活。该提案的主要目的是研究 RGS 蛋白在调节心脏肥大生长程序中的生理作用。中心假设是RGS蛋白决定心肌细胞对细胞外刺激的反应性，并且RGS基因表达增加作为限制G蛋白介导的信号转导的适应性机制。在最初的资助期间，我们证明了 RGS 蛋白存在于心脏中，RGS3 和 RGS4 基因表达对外部刺激有反应，RGS4 在小鼠体内的心脏特异性过度表达可以阻止压力超负荷和运动引起的心脏肥大，并且 RGS4 是体内心脏中 Gq 的 GAP。尽管有这些发现，关于 RGS 蛋白在心脏病中的作用仍然存在许多问题。在该项目的下一阶段，我们建议通过在培养细胞中使用“敲低”策略来研究 RGS2、RGS3 和 RGS4 在心肌细胞肥大中的具体作用。其次，我们通过使用全身和心脏特异性靶向破坏 RGS4 基因的小鼠，研究了 RGS4 在压力超负荷和运动引起的心脏肥大中的具体作用。第三，我们通过全身靶向破坏 RGS3 基因的小鼠，研究了 RGS3 在压力超负荷和运动引起的心脏肥大中的具体作用。这些实验将有助于明确 RGS 蛋白在心脏肥大和收缩功能障碍发病机制中的作用，并可能为新型治疗药物的开发提供重要信息。