心肌梗死后大量心肌细胞因凋亡而丢失是其导致心力衰竭和临床死亡的病理基础，G蛋白偶联受体(GPCR)的过度磷酸化在其中发挥重要作用，GPCR激酶(GRK)在心梗后表达升高是其主要原因。GRK4与高血压等心血管疾病关系密切，在心梗后表达增加，但是否参与心梗后心肌细胞凋亡尚不清楚。我们通过GRK4过表达和敲除小鼠发现GRK4加重心梗后心肌细胞凋亡。鉴于自噬和凋亡关系密切，我们通过预实验发现GRK4通过下调自噬关键基因beclin1抑制自噬。HDAC4是beclin1表达的关键调控因子，我们的初步研究发现GRK4可通过磷酸化HDAC4抑制其活性。因此我们提出假设：GRK4通过与HDAC4作用将其磷酸化，促进其向核外转运，抑制HDAC4对belcin1的转录上调作用，进而减弱自噬，加重心肌细胞凋亡与心肌重塑。本项目旨在揭示GRK4通过HDAC4加重心梗死后缺血损伤的机制，并为其防治提供潜在靶点。

The cell loss caused by apoptosis after myocardial infarction (MI) is the pathological basis of the post-MI heart failure and death. A wealth of evidence supported that the over phosphorylation of G-protein-coupled receptor (GPCR) play a vital role in this process. Previous studies revealed that the elevated G-protein-coupled receptor kinases (GRKs) contributed to the GPCR over phosphorylation. GRK4 has been reported to play a regulatory role in hypertension and expressed in heart, but little is known of its role in cardiomyocytes and myocardial infarction. In GRK4-knock-out mouse and GRK4 transgenic mouse line, we have found that GRK4 is an essential regulator for post-MI cardiomyocyte apoptosis. Autophagy is a physiological and cellular process tightly connected to apoptosis under stress, we observed that the repressed beclin-1 and autophagy cause by GRK4 overexpression is responsible for the exaggerated post-MI cardiomyocyte apoptosis..The expression of beclin1 is regulated by Histone deacetylase 4 (HDAC4), our work demonstrated that GRK4 can phosphorylate HDAC4 and thus repress its activity. Therefore we proposed that GRK4 increases cardiomyocyte injury caused by MI by inhibiting autophagy and promoting cardiomyocyte apoptosis. These GRK4 effects are mediated by phosphorylation of HDAC4 and a decrease in beclin1 expression. This work aim to investigate the mechanisms by which GRK4 impact on autophagy, apoptosis and post-MI cardiac remodeling, and to provide GRK4 as a potential therapeutic target for MI.