The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction
The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction
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DOI：
10.1093/eurheartj/ehaa878
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发表时间：
2021-04-07
影响因子：
39.3
通讯作者：
Zeng, Chunyu
中科院分区：
文献类型：
--
作者：
Li, Liangpeng;Fu, Wenbin;Zeng, Chunyu
G蛋白偶联受体激酶4（GRK 4）在高血压中起重要作用，但其在心肌细胞和心肌梗死中的作用尚不清楚。本研究的目的是探讨GRK 4在MI发病机制和进展中的作用。方法和结果我们研究了GRK 4在MI后小鼠心脏的表达和分布模式。产生GRK 4 A486 V转基因小鼠，可诱导的心肌细胞特异性GRK 4敲除小鼠，并与其对照小鼠一起进行MI。评估心肌梗死、心功能、心肌细胞凋亡、自噬活性和HDAC 4磷酸化。MI后心肌GRK 4的mRNA和蛋白水平均升高。过表达人GRK 4野生型（WT）或人GRK 4 A486 V变体的转基因小鼠具有增加的心肌梗死、加重的心功能障碍和重构。相反，心肌细胞特异性GRK 4基因敲除小鼠MI诱导的心功能障碍和重构得到改善。GRK 4在心肌细胞中的过表达加重了细胞凋亡，抑制了自噬，并降低了beclin-1的表达，这部分被自噬激动剂雷帕霉素所挽救。MI还诱导GRK 4的核转位，GRK 4通过增加HDAC 4磷酸化和减少其与beclin-1启动子的结合来抑制自噬。HDAC 4 S632 A突变部分恢复GRK 4诱导的自噬抑制。结论GRK 4可能通过抑制心肌细胞自噬和促进心肌细胞凋亡而加重心肌梗死时心肌细胞的损伤。这些作用是由HDAC 4的磷酸化和beclin-1表达的减少介导的。
Aims G protein-coupled receptor kinase 4 (GRK4) has been reported to play an important role in hypertension, but little is known about its role in cardiomyocytes and myocardial infarction (MI). The goal of present study is to explore the role of GRK4 in the pathogenesis and progression of MI.Methods and results We studied the expression and distribution pattern of GRK4 in mouse heart after MI. GRK4 A486V transgenic mice, inducible cardiomyocyte-specific GRK4 knockout mice, were generated and subjected to MI with their control mice. Cardiac infarction, cardiac function, cardiomyocyte apoptosis, autophagic activity, and HDAC4 phosphorylation were assessed. The mRNA and protein levels of GRK4 in the heart were increased after MI. Transgenic mice with the overexpression of human GRK4 wild type (WT) or human GRK4 A486V variant had increased cardiac infarction, exaggerated cardiac dysfunction and remodelling. In contrast, the MI-induced cardiac dysfunction and remodelling were ameliorated in cardiomyocyte-specific GRK4 knockout mice. GRK4 overexpression in cardiomyocytes aggravated apoptosis, repressed autophagy, and decreased beclin-1 expression, which were partially rescued by the autophagy agonist rapamycin. MI also induced the nuclear translocation of GRK4, which inhibited autophagy by increasing HDAC4 phosphorylation and decreasing its binding to the beclin-1 promoter. HDAC4 S632A mutation partially restored the GRK4-induced inhibition of autophagy. MI caused greater impairment of cardiac function in patients carrying the GRK4 A486V variant than in WT carriers.Conclusion GRK4 increases cardiomyocyte injury during MI by inhibiting autophagy and promoting cardiomyocyte apoptosis. These effects are mediated by the phosphorylation of HDAC4 and a decrease in beclin-1 expression.