含缬酪肽蛋白改善压力超负荷导致的心肌损伤和心力衰竭的机制研究

压力超负荷引起的心肌损伤是高血压导致心力衰竭的主要原因，但机制不明。研究显示含缬酪肽蛋白（VCP）可减少缺氧诱导的心肌凋亡。我们发现心衰病人和小鼠心肌VCP含量下降，过表达VCP可改善压力超负荷心衰小鼠的心功能，并增强心肌mTOR雷帕霉素不敏感伴侣蛋白Rictor的活性。因此我们推测：压力超负荷条件下，VCP与Rictor结合并维持Rictor活性是VCP保护心肌细胞和改善心功能的核心机制。本项目将探讨心衰患者血清VCP含量和心功能的关系，并在功能增强和缺失型VCP转基因小鼠及腺病毒干预的心肌细胞中制备体内、外压力超负荷模型，证实VCP改善压力超负荷导致的心肌损伤和心衰，并通过双分子荧光互补等技术明确VCP与Rictor的直接结合关系和关键结构域，阐明VCP在压力超负荷下发挥内源性心肌保护作用的信号通路等分子机制，为心衰的临床诊断发掘新的血清标志物并提供新的治疗靶点。

Pressure overload-induced myocardial injury is the dominant cause of heart failure led by hypertension. However, the underlying mechanism remains unclear. Studies have shown that valosin-containing protein (VCP) reduced hypoxia-induced myocardial apoptosis. We found that the content of VCP in myocardium of heart failure patients and mice was decreased dramatically. Over-expression of VCP notably alleviated cardiac remodeling and heart failure in mice subjected to chronic pressure overload. The activity of rapamycin-insensitive chaperone Rictor of mTOR was enhanced by over-expression of VCP. We here hypothesized that VCP binds with Rictor and maintains its activity, which is the key endogenous mechanism of VCP protecting myocardial and alleviating heart failure induced by pressure overload. The purpose of this study is to investigate the relationship between serum VCP levels and cardiac function in patients with heart failure, as well as the molecular mechanism by which VCP protects cardiomyocytes and rescues cardiac function from chronic pressure overload. We will establish pressure overload models in transgenic mice with gain or loss of function of VCP in cardiomyocytes in vivo, as well as in cultured cardiomyocytes interfered with adenoviruses in vitro. The present study will illuminate the cardio-protection of VCP, identify the interaction and key binding sites between VCP and Rictor and discuss the relationship between the binding and the myocardial protective effect of VCP. Through this project, it is expected to clarify the mechanism by which VCP improves myocardial injury and heart failure induced by pressure overload, explore a novel serum biomarker of heart failure, and provide a new target for the treatment of heart failure.