基于β-arrestin介导的β1受体偏向激活研究AACO方促进心肌肌质网钙泵防治慢性心衰的作用机制

促进心肌肌质网钙泵表达和活性一直是慢性心衰防治研究的重要方向。课题组前期运用均匀设计筛选并证实黄芪甲苷、乌头碱、姜黄素、麦冬皂苷D特定配比复方-AACO方显著改善慢性心衰并促进心肌肌质网钙泵，但机制并不清楚。转录组mRNA芯片研究发现该方能上调衰竭心肌β1受体和β-arr2的表达。结合新认识“β-arrestin介导的β1受体偏向激活调控心肌肌质网钙泵翻译后修饰”，提出“AACO方促进β-arrestin介导的β1受体偏向激活改善衰竭心肌肌质网钙泵”的假说。拟采用胸主动脉缩窄模型（β1AR、βarr1、βarr2基因敲除）和急、慢性衰竭心肌细胞（肾上腺素、胸主动脉缩窄诱导），围绕β1受体偏向激活信号通路及肌质网钙泵翻译后修饰调节的关键环节，解析AACO方调控β-arrestin介导的β1受体偏向激活改善心肌肌质网钙泵的作用机制，以明确该方治疗慢性心衰的关键靶位和机制，为今后研发新药奠定基础

Improving the expression and activity of SERCA2a has always been an important direction in the prevention and treatment of chronic heart failure. Our group used the uniform design to screen out the AACO compound which is composed of Astragalus (A), Aconitine (A), Curcumin (C) and Ophiopogon D（O）. We also confirmed that the AACO compound is effective in treating chronic heart failure by improving the expression and activity of SERCA2a. However, how the AACO compound promoting SERCA2a in heart failure remains unclear. It was found that AACO compound can up-regulate the expression of β1 receptor and β-arr2 in the failing myocardium screened by the gene microarray. There is a new concept of “ β1AR-β-arrestin-biased agonism can promote SERCA2a SUMOylation to improve chronic heart failure ”. Based on this concept, we hypothesized that AACO compound may improve the expression and activity of SERCA2a through β1AR-β-arrestin-biased agonism. To confirm this hypothesis, we intend a study which includes in vivo experiment (chronic heart failure model induced by thoracic aortic coarctation in C57BL/6、β1-AR KO, β-arr2 KO and β-arr1 KO mouse) and in intro experiment (primary adult cardiomyocytes isolated in acute heart failure induced by adrenaline administrating or chronic heart failure model induced by thoracic aortic coarctation) .Focusing on the key link of β1-AR-β-arrestin-biased agonism and post-translational modification of SERCA2a, we intend to pursue the mechanism of AACO compound improving the expression and activity of SERCA2a through β-arrestin-biased agonism. Thus, we can clarify the key targets and mechanisms of AACO compound in treating chronic heart failure. This study also lays the foundation of new drug development in chronic heart failure.