压力超负荷和容量超负荷所致心脏肥大中β-arrestin-2的作用差异及其机制的研究

压力超负荷和容量超负荷均产生机械应力刺激心脏肥大，但压力超负荷引起向心性肥大，容量超负荷引起离心性肥大，其差异机制有待阐明。我们的研究显示，心脏肥大信号起始因子β-arrestin-2在压力超负荷心脏中表达更显著；并且在压力超负荷下，与野生型小鼠相比，兰尼碱2型受体（RyR-2）基因敲除小鼠的心脏更多趋向容量超负荷心脏改变，提示了β-arrestin-2和RyR-2在压力超负荷和容量超负荷心肌肥厚差异机制中的作用。本研究拟通过缩窄主动脉和破坏主动脉瓣，分别建立小鼠压力超负荷和容量超负荷模型，观察两者心脏β-arrestin-2和RyR-2表达差异；通过基因转染/敲低分别上/下调β-arrestin-2和RyR-2，观察压力超负荷和容量超负荷心脏以及RyR-2和β-arrestin-2变化，阐明β-arrestin-2和RyR-2在压力超负荷和容量超负荷心脏不同肥厚表型中的调控作用和机制。

Both pressure overload and volume overload exert mechanical stress on the heart to stimulate cardiac hypertrophy, while pressure overload induces concentric cardiac hypertrophy and volume overload produces eccentric cardiac hypertrophy. Mechanisms for that discrepancy remain to elucidate. Our previous studies showed that β-arrestin-2, a hypertrophic signal initiator in the heart, was more significantly expressed in the pressure overload heart, and, under pressure overload, the heart of ryanodine receptor type 2 (RyR-2) knockout mice but not wild type mice, showed the transition to volume overload heart, suggesting β-arrestin-2 and RyR-2 play roles in the differentiation of cardiac hypertrophy induced by pressure overload and volume overload. This project aims to establish pressure overload model by constriction of aortic artery and volume overload model by disruption of aortic valve in mice, observe the impact of the two types of overloads on β-arrestin-2 and RyR-2 expression; investigate the variation of cardiac hypertrophy, myocardial RyR-2 and β-arrestin-2 after respective upregulation/downregulation of β-arrestin-2 and RyR-2 via gene transfection/knockout, cast lights on the elucidation of roles of β-arrestin-2 and RyR-2 in the differentiation of two forms of overload induced cardiac hypertrophy.