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: 7796555
• 负责人: Guo-Chang Fan
• 金额: $ 39万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-18 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796555
• 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）：心脏病是全球主要的死亡原因。越来越多的证据表明，细胞凋亡，与有害的结构和功能的改变，是一个主要的贡献者在心脏重塑和心力衰竭的进展。因此，防止心肌细胞的损失对于维持正常的心脏功能变得至关重要。然而，如果抑制心肌细胞死亡仅仅导致功能失调的心肌细胞的存活增加，那么它将几乎没有临床前景。我们最近的研究表明，小的热休克蛋白Hsp 20可以改善心脏功能，并提供保护心肌细胞死亡。Hsp 20与sHsps的其他成员的不同之处在于：1）它调节血管舒张和心肌收缩：2）Hsp 20过表达对β激动剂诱导的细胞凋亡和缺血/再灌注损伤具有保护作用;和3）Hsp 20含有独特的PKA/PKG磷酸化位点，RRAS，和该位点的磷酸化，显著增加心肌细胞的收缩力和心脏保护。在这个项目中，我们提出了进一步的研究，以阐明在体内的作用，热休克蛋白20及其磷酸化的心肌收缩力，使用基因改变的小鼠模型。此外，由于Hsp 20及其磷酸化水平的改变调节心脏对应激的反应，我们建议进一步研究Hsp 20和特异性磷酸化Hsp 20在心脏重构过程中对压力超负荷和心肌梗死的反应。我们还建议使用体内心脏基因递送来确定Hsp 20在预先存在的心力衰竭中的治疗意义。这些研究将提供重要的信息心脏热休克蛋白20在体内的生理和病理生理条件下的功能作用。总体而言，我们提出的研究将：a）推进我们对Hsp 20调节心肌收缩力和凋亡细胞死亡的机制的认识;和B）提供有价值的见解Hsp 20在心脏病中的潜在益处。