β-adrenergic activation may promote myosin light chain kinase degradation through calpain in pressure overload-induced cardiac hypertrophy

Biomedicine & Pharmacotherapy

卷:129

Gang Wu¹  Xiaoling Su²  Shun Wang³  Shuai Mao³  Congxin Huang³  Le Wang³  He Huang³  Beilei Liu³  Hui Yan³  Haixiong Wang⁴  Mian Cheng⁵ 

[1] Corresponding author at: Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430074, China.;

[2] Department of Cardiology, Qinghai Provincial People's Hospital, Xining, 810007, China;

[3] Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Hubei Key Laboratory of Cardiology, Wuhan, 430060, China;

[4] Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, 030001, China;

[5] Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430074, China;

关键词: Cardiac hypertrophy;    β-adrenergic activity;    Myosin light chain kinase;    Calpain;   

DOI  :  

来源: DOAJ

【 摘 要 】

Background: β-adrenergic activation is able to exacerbate cardiac hypertrophy. Myosin light chain kinase (MLCK) and its phosphorylated substrate, phospho-myosin light chain 2 (p-MLC2), play vital roles in regulating cardiac hypertrophy. However, it is not yet clear whether there is a relationship between β-adrenergic activation and MLCK in the progression of cardiac hypertrophy. Therefore, we explored this relationship and the underlying mechanisms in this work. Methods: Cardiac hypertrophy and cardiomyocyte hypertrophy were induced by pressure overload and isoproterenol (ISO) stimulation, respectively. Echocardiography, histological analysis, immunofluorescence and qRT-PCR were used to confirm the successful establishment of the models. A β-blocker (metoprolol) and a calpain inhibitor (calpeptin) were administered to inhibit β-adrenergic activity in rats and calpain in cardiomyocytes, respectively. The protein expression levels of MLCK, myosin light chain 2 (MLC2), p-MLC2, myosin phosphatase 2 (MYPT2), calmodulin (CaM) and calpain were measured using western blotting. A cleavage assay was performed to assess the degradation of recombinant human MLCK by recombinant human calpain. Results: The β-blocker alleviated cardiac hypertrophy and dysfunction, increased MLCK and MLC2 phosphorylation and decreased calpain expression in pressure overload-induced cardiac hypertrophy. Additionally, the calpain inhibitor calpeptin attenuated cardiomyocyte hypertrophy, upregulated MLCK and p-MLC2 and reduced MLCK degradation in ISO-induced cardiomyocyte hypertrophy. Recombinant human calpain degraded recombinant human MLCK in vitro in concentration- and time-dependent manners, and this degradation was inhibited by the calpain inhibitor calpeptin. Conclusion: Our study suggested that β-adrenergic activation may promote the degradation of MLCK through calpain in pressure overload-induced cardiac hypertrophy.

【 授权许可】

Unknown