Physiological and Pathophysiological Roles of Hsp20 in the Heart

Hsp20 在心脏中的生理和病理生理作用

• 批准号: 7837486
• 负责人: Guo-Chang Fan
• 金额: $ 26.73万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837486
• 关键词: Acute; Agonist; Apoptosis; Apoptotic; Attenuated; Cardiac; Cardiac Myocytes; Cause of Death; Cell Death; Cessation of life; Clinical; Cyclic AMP; Down-Regulation; Etiology; Gene Delivery; Gene Transfer; Generations; Goals; Heart; Heart Diseases; Heart failure; Heat shock proteins; In Vitro; Injury; Ischemia; Knock-out; Knowledge; Maintenance; Mediating; Modeling; Morbidity - disease rate; Myocardial; Myocardial Infarction; Pathogenesis; Pathway interactions; Phosphorylation; Phosphorylation Site; Physiological; Process; Proteins; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Role; Signal Transduction; Stimulus; Stress; Therapeutic; Transgenic Model; Transgenic Organisms; Vasodilation; functional restoration; improved; in vivo; insight; member; mortality; mouse model; mutant; overexpression; pressure; prevent; programs; protective effect; response

DESCRIPTION (provided by applicant): Heart disease is a leading cause of death worldwide. Increasing evidence indicates that apoptosis, associated with detrimental structural and functional alterations, is a major contributor in the progression of cardiac remodeling and heart failure. Thus, preventing the loss of cardiomyocytes becomes critical for the maintenance of normal cardiac function. However, inhibition of cardiac cell death would hold little clinical promise, if it simply resulted in increased survival of dysfunctional cardiomyocytes. Our recent studies suggest that the small heat-shock protein Hsp20 may improve cardiac function and provide protection against cardiomyocyte death. Hsp20 is different from the other members of sHsps in the following respects: 1) It regulates both vasorelaxation and cardiac contractility; 2) Overexpression of Hsp20 provides cardioprotection against p-agonist-induced apoptosis and ischemia/reperfusion-induced injury; and 3) Hsp20 contains a unique PKA/PKG phosphorylation site, RRAS, and phosphorylation of this site, significantly increases contractility and cardioprotection in cardiomyocytes. In this project, we propose further studies to elucidate the in vivo role of Hsp20 and its phosphorylation in cardiac contractility, using genetically altered mouse models. Furthermore, since alterations in the levels of Hsp20 and its phosphorylation regulate the heart's responses to stress, we propose to further investigate the efficacy of Hsp20 and specifically phosphorylated Hsp20 in the heart's remodeling process in response to pressure-overload and myocardial infarction. We also propose to determine the therapeutic significance of Hsp20 in the setting of pre-existing heart failure, using in vivo cardiac gene delivery. These studies will provide important information on the functional role of cardiac Hsp20 in vivo under physiological and pathophysiological conditions. Overall, our proposed studies will: a) advance our knowledge on the mechanisms underlying regulation of cardiac contractility and apoptotic cell death by Hsp20; and b) provide valuable insights into the potential benefits of Hsp20 in heart disease.

描述（由申请人提供）：心脏病是全球死亡的主要原因。越来越多的证据表明，与有害结构和功能改变有关的凋亡是心脏重塑和心力衰竭进展的主要因素。因此，防止心肌细胞的丧失对于维持正常心脏功能至关重要。但是，如果仅导致功能失调的心肌细胞生存率增加，对心脏细胞死亡的抑制作用将几乎没有临床承诺。我们最近的研究表明，小型热蛋白HSP20可以改善心脏功能并提供防止心肌细胞死亡的保护。在以下方面，HSP20与SHSP的其他成员不同：1）它调节血管延缓和心脏收缩率； 2）HSP20的过表达可针对P-激动剂诱导的凋亡和缺血/再灌注诱导的损伤提供心脏保护； 3）HSP20包含独特的PKA/PKG磷酸化位点，RRA和该部位的磷酸化，可显着增加心肌细胞中的收缩力和心脏保护性。在该项目中，我们提出了进一步的研究，以使用遗传改变的小鼠模型阐明HSP20的体内作用及其在心脏收缩性中的磷酸化作用。此外，由于HSP20水平的改变及其磷酸化调节了心脏对压力的反应，因此我们建议进一步研究HSP20及其在心脏重塑过程中特异性磷酸化的HSP20的疗效，以响应压力超负荷和心肌梗死。我们还建议使用体内心脏基因递送在预先存在的心力衰竭的情况下确定HSP20的治疗意义。这些研究将提供有关在生理和病理生理条件下心脏HSP20在体内功能作用的重要信息。总体而言，我们提出的研究将：a）提高我们对HSP20对心脏收缩性和凋亡细胞死亡的机制的了解； b）为HSP20在心脏病中的潜在益处提供宝贵的见解。