Regulation of cardiac stress responses by Rho kinase

Rho 激酶调节心脏应激反应

• 批准号: 8437310
• 负责人: Lei Wei
• 金额: $ 37.13万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437310
• 关键词: Actins; Address; Adverse effects; Age-Months; Angiotensin II; Animal Model; Apoptosis; Apoptotic; Biology; Cardiac; Cardiac Death; Cardiac Myocytes; Cardiotoxicity; Cell Adhesion; Cell Death; Cell Survival; Cells; Cerebrovascular Spasm; Cessation of life; Characteristics; Chronic; Clinic; Clinical Research; Clinical Trials; Cytoskeleton; Data; Dilated Cardiomyopathy; Disease; Doxorubicin; Embryo; Etiology; Exhibits; Family; Fibroblasts; Fibrosis; Focal Adhesion Kinase 1; Functional disorder; Genetic Processes; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Heart Diseases; Heart Hypertrophy; Heart failure; Human; In Vitro; Infusion procedures; Japan; Knockout Mice; Knowledge; LIMK1 gene; Left; Left Ventricular Hypertrophy; Mediating; Modeling; Mus; Myosin ATPase; Names; Pathogenesis; Pathologic; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Protein Isoforms; ROCK1 gene; Regulation; Research; Rho-associated kinase; Role; Signal Transduction; Specificity; Stimulus; Stress; Structure; Subarachnoid Hemorrhage; Sudden Death; Takeda brand of pioglitazone hydrochloride; Testing; Therapeutic Intervention; Ventricular; bench to bedside; biological adaptation to stress; cofilin; design; effective therapy; fasudil; human disease; human morbidity; human mortality; improved; in vivo; inhibitor/antagonist; insight; kinase inhibitor; member; novel; polymerization; pressure; prevent; public health relevance; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Heart failure remains a leading cause of human morbidity and mortality. Rho kinase (also named ROCK) has recently emerged as a potential therapeutic target for the treatment of cardiac diseases with the overall promising studies showing beneficial effects of ROCK inhibitors in experimental and clinical studies. However, one important question needing to be addressed is whether ROCK truly represents a viable target for the treatment of human disease as currently available ROCK inhibitors have broad specificity. In addition, the two members of the ROCK family, ROCK1 and ROCK2, are inhibited by ROCK inhibitors with equal potency, and little is known about ROCK isoform functions in vivo. We recent discovered that systemic ROCK1 deficiency is protective against cardiac decompensation and the anti-apoptotic effect of ROCK1 deficiency is a critical contributor. In contrast to the beneficial effects of ROCK1 deletion, we observed that cardiac-specific ROCK2 deficiency results in spontaneous cardiac hypertrophy and dysfunction, suggesting a novel role for ROCK2 in cardiac protection. Our in vitro studies using ROCK1 or ROCK2 deficient embryo-derived fibroblasts support a novel mechanistic concept that ROCK1 preferentially mediates stress-induced acto-myosin contraction via the ROCK1/MYPT/MLC pathway leading to increased cell death, while ROCK2 preferentially contributes to actin polymerization via the ROCK2/LIMK/cofilin pathway leading to improved cell survival under stress conditions. The goal of this application is to dissect isoform functions of ROCK in hypertrophic cardiac remodeling and to test a novel central hypothesis that ROCK1 and ROCK2 are functionally different in regulating cardiomyocyte death and cardiac remodeling in response to cardiac stress. Specific Aim 1 will test the hypothesis that ROCK2 promotes cardiomyocyte survival and cardiac protection. The studies will further characterize the onset and progression of spontaneous cardiac hypertrophy in cardiac-specific ROCK2 knockout mice, and will determine if conditional ROCK2 deletion in cardiomyocytes accelerates heart failure progression. Specific Aim 2 will determine the ultimate role of ROCK1 in cardiac decompensation. The studies will determine if conditional ROCK1 deletion in cardiomyocytes can limit the progression of heart failure when cardiac hypertrophy or dilated cardiomyopathy has already occurred through chronic pressure overload. Specific Aim 3 will test the hypothesis that ROCK1 and ROCK2 play opposite roles in mediating stress-induced cardiomyocyte death and characterize the underlying mechanisms. Results of these studies will significantly advance our knowledge in ROCK isoform pathophysiology and inform clinical trials testing ROCK pan- inhibitors, and eventually isoform selective inhibitors, with the ultimate goal of developing therapeutic interventions to prevent cardiomyocyte death and reduce heart failure progression.

描述（由申请人提供）：心力衰竭仍然是人类发病率和死亡率的主要原因。Rho激酶（也称为ROCK）最近已经成为用于治疗心脏疾病的潜在治疗靶标，总体上有希望的研究显示ROCK抑制剂在实验和临床研究中的有益效果。然而，需要解决的一个重要问题是ROCK是否真正代表了治疗人类疾病的可行靶标，因为目前可用的ROCK抑制剂具有广泛的特异性。此外，ROCK家族的两个成员ROCK 1和ROCK 2被具有相同效力的ROCK抑制剂抑制，并且对ROCK同种型在体内的功能知之甚少。我们最近发现，系统性ROCK 1缺乏对心脏失代偿具有保护作用，ROCK 1缺乏的抗凋亡作用是一个关键因素。与ROCK 1缺失的有益作用相反，我们观察到心脏特异性ROCK 2缺陷导致自发性心脏肥大和功能障碍，这表明ROCK 2在心脏保护中的新作用。我们使用ROCK 1或ROCK 2缺陷的胚胎来源的成纤维细胞的体外研究支持一种新的机制概念，即ROCK 1优先通过ROCK 1/MYPT/MLC途径介导应激诱导的肌动蛋白-肌球蛋白收缩，导致细胞死亡增加，而ROCK 2优先通过ROCK 2/LIMK/cofilin途径促进肌动蛋白聚合，导致应激条件下细胞存活改善。本申请的目的是剖析ROCK在肥厚性心脏重塑中的同种型功能，并测试一个新的中心假设，即ROCK 1和ROCK 2在调节心肌细胞死亡和响应心脏应激的心脏重塑中功能不同。具体目标1将检验ROCK 2促进心肌细胞存活和心脏保护的假设。这些研究将进一步表征心脏特异性ROCK 2敲除小鼠中自发性心脏肥大的发作和进展，并将确定心肌细胞中的条件性ROCK 2缺失是否加速心力衰竭进展。具体目标2将确定ROCK 1在心脏失代偿中的最终作用。这些研究将确定当心脏肥大或扩张型心肌病已经通过慢性压力超负荷发生时，心肌细胞中的条件性ROCK 1缺失是否可以限制心力衰竭的进展。具体目标3将测试ROCK 1和ROCK 2在介导应激诱导的心肌细胞死亡中发挥相反作用的假设，并表征其潜在机制。这些研究的结果将显著推进我们在ROCK亚型病理生理学方面的知识，并为测试ROCK泛抑制剂和最终亚型选择性抑制剂的临床试验提供信息，最终目标是开发预防心肌细胞死亡和减少心力衰竭进展的治疗干预措施。