压力超负荷通过激活肾素血管紧张素系统以及交感神经系统导致心肌胰岛素抵抗并最终引起心脏功能障碍。前期研究意外发现在血管紧张素II受体1和β1肾上腺能受体缺失的COS7细胞中压力超负荷仍可以诱导胰岛素受体（InsR）的异常磷酸化并引起Akt/PI3K信号通路损伤。因此我们推测InsR可直接感受机械信号并诱发心肌细胞胰岛素抵抗、心肌损伤和功能障碍。本项目将在此发现的基础上，通过基因敲除或SiRNA在体内、外实验中证实机械刺激可以直接诱导InsR磷酸化，并明确其磷酸化位点。本研究将构建不同的InsR突变体以确定其机械感受位点，并研究在机械刺激诱导InsR磷酸化后心肌细胞内胰岛素信号通路改变以及对心肌细胞胰岛素敏感性和心肌肥大的影响。本研究将论证InsR是新的心肌细胞机械刺激感受器，是心脏压力超负荷与心肌胰岛素抵抗之间的直接桥梁，并为高血压心肌损伤的防治提供新的理论依据。

Pressure overload leads to myocardial insuln resistance by activating the synthethic system as well as the renin-angiotensin system,and eventually, provokes cardiac dysfunction. Unexpectedly, our preliminary data indicate that pressure overload induces abnormal phosphorylation of insulin receptor and insulin receptor substrates 1(IRS1)/Ankt/PI3K signal pathway independent of insulin in cells without endogenous angiotensin II receptor 1 (AT1R) and β1 adrenergic receptor. Therefore we conclude that insulin receptor can response to the mechanical stimulation independent of insulin and convert it into intracellular biochemical signals which induces insulin resistance and cell dysfuction. The present project will further explore the direct response of insulin receptor by mechanical stress and then determine the phosphorylation sites of insulin receptor by using SiRNA and AT1R knockout mouse in vitro and in vivo studies. Different insulin receptor mutants will be constructed so as to confirm the site of mechnosensor. We also plan to investigate the changes of the intracellular insulin signal pathway and their effects on the myocardial insulin sensitivity and hypertrophy. The present study will prove insulin receptor as a new mecahnosensor and provide evidences of direct link between cardiac pressure overload and myocardial insulin resistance which will be useful for the management of hypertension against myocardial injury.