Physiological and Pathophysiological Roles of Hsp20 in the Heart

描述（由申请人提供）：心脏病是世界范围内死亡的主要原因。越来越多的证据表明，细胞凋亡与有害的结构和功能改变有关，是心脏重塑和心力衰竭进展的主要因素。因此，防止心肌细胞的损失对于维持正常的心脏功能至关重要。然而，如果抑制心肌细胞死亡只是导致功能失调的心肌细胞存活增加，那么它的临床前景就不大。我们最近的研究表明，小热休克蛋白Hsp20可能改善心功能，并提供防止心肌细胞死亡的保护。Hsp20与其他sHsps成员的不同之处在于：1)它既调节血管舒张又调节心脏收缩力；2)过表达Hsp20对p激动剂诱导的细胞凋亡和缺血/再灌注诱导的损伤具有心脏保护作用；3) Hsp20含有独特的PKA/PKG磷酸化位点RRAS，该位点的磷酸化可显著提高心肌细胞的收缩性和心脏保护作用。在这个项目中，我们提出进一步的研究，以阐明Hsp20及其磷酸化在心脏收缩性中的体内作用，使用转基因小鼠模型。此外，由于Hsp20水平的改变及其磷酸化调节心脏对应激的反应，我们建议进一步研究Hsp20及其特异性磷酸化Hsp20在压力过载和心肌梗死时心脏重塑过程中的作用。我们还建议通过体内心脏基因传递来确定Hsp20在既往心力衰竭患者中的治疗意义。这些研究将为心脏Hsp20在体内生理和病理生理条件下的功能作用提供重要信息。总的来说，我们提出的研究将：a)提高我们对Hsp20调控心脏收缩力和凋亡细胞死亡的机制的认识；b)对热休克蛋白20对心脏病的潜在益处提供有价值的见解。

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.