心梗及其并发症心衰是威胁人类健康的重大疾病，心梗后心脏的不良重构是导致心功能恶化的重要因素。近来研究表明心梗后交感肾上腺素能神经系统（SAS）和肾素-血管紧张素系统（RAS）激活可以通过β-arrestins信号产生心脏保护作用，但机制不清。此外，研究发现心梗后心肌细胞自噬增强，且对心梗预后有保护作用。我们发现心肌细胞β-arrestin-1条件敲除后心梗预后变差，其机制与抑制β-arrestin-1介导的心肌细胞自噬有关。本项目拟在细胞、器官及整体动物水平研究β-arrestins对心肌细胞的直接保护作用，并探索激活β-arrestins信号的上游受体机制，及其下游与自噬的关系。本研究将为开发具有β-arrestins偏向性的心衰治疗药物提供思路。

Myocardial infarction (MI) and ensuing heart failure area major threat to our health. Adverse myocardial remodeling of post-MI hearts results in cardiac dysfunction. In recent years, it has been reported that after MI, the activation of sympathetic/adrenergic nervous system (SAS) and renin-angiotensin system (RAS) exerts a cardioprotective effect through β-arrestin-dependent signaling pathways. However, the underlying mechanism remains unclear. Moreover, it has been reported that after MI, autophagy in cardiomyocytes is enhanced, which may contribute to cardioprotection and improve the prognosis of MI. Our preliminary study showed that cardiomyocyte-specific knockout of β-arrestin-1 results in worse cardiac remodeling and function after MI, which was associated with reduced cardiomyocyte autophagy. This project aims to study direct protective effects of β-arrestins on stressed cardiomyocytes with cultured cardiomyocytes, ex vivo hearts and in vivo MI models. We will further explore the upstream mechanisms that activate β-arrestin-dependent signaling pathways via G-protein coupled receptors as well as the downstream mechanism regulating autophagy in stressed cardiomyocytes and hearts. This study will provide novel insight for developing β-arrestin-biased drugs to treat heart failure.