Regulation of cardiac stress responses by Rho kinase

Rho 激酶调节心脏应激反应

• 批准号: 8665458
• 负责人: Lei Wei
• 金额: $ 38.22万
• 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/8665458
• 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（也被称为Rock）最近成为治疗心脏病的潜在治疗靶标，其整体有前途的研究表明岩石抑制剂在实验和临床研究中的有益作用。但是，需要解决的一个重要问题是，岩石是否真正代表了治疗人类疾病的可行目标，因为目前可用的岩石抑制剂具有广泛的特异性。此外，岩石家族的两个成员Rock1和Rock2受到同等效力的岩石抑制剂的抑制，对体内的岩石同工型功能知之甚少。我们最近发现，全身Rock1缺乏症可以防止心脏代偿化，而Rock1缺乏症的抗凋亡作用是至关重要的。与Rock1缺失的有益作用相反，我们观察到心脏特异性的Rock2缺乏会导致心脏肥大和功能障碍，这表明Rock2在心脏保护中起了新的作用。我们使用Rock1或Rock2缺乏胚胎衍生的成纤维细胞进行的体外研究支持了一种新型的机械概念，该概念通过Rock1/MyPT/MyPT/MLC途径优先介导了压力诱导的acto肌球蛋白收缩，从而导致细胞死亡增加，而Rock2通过Rock2通过Rock2/limk/limk/limk/Cofilin pation rock2促进了Rock2的生存途径。该应用的目的是在肥厚的心脏重塑中剖析岩石的同工型功能，并测试一种新的中心假设，即Rock1和Rock2在调节心肌细胞死亡和对心脏应激的心脏重塑方面在功能上有所不同。具体目标1将检验Rock2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Rock2敲除小鼠自发性心脏肥大的发作和进展，并确定心肌细胞中有条件的Rock2缺失是否会加速心力衰竭的进展。具体目标2将决定Rock1在心脏代偿上的最终作用。研究将确定心肌细胞中有条件的岩石1缺失是否会限制心脏肥大或扩张性心肌病的发展，这是通过慢性压力超负荷发生的。特定的目标3将检验以下假设：Rock1和Rock2在介导压力诱导的心肌细胞死亡并表征基本机制中起着相反的作用。这些研究的结果将显着提高我们在岩石同工型病理生理学方面的知识，并为临床试验测试岩石抑制剂，并最终提高同工型选择性抑制剂，其最终目的是开发治疗性干预措施以防止心肌细胞死亡并减少心脏衰竭。