磷酸化
肌肉肥大
基因敲除
病态的
心力衰竭
激酶
内科学
医学
心功能曲线
内分泌学
生物
细胞生物学
细胞凋亡
生物化学
作者
Jian Huang,Luxin Wang,Yunli Shen,Shengqi Zhang,Ya‐Qun Zhou,Jimin Du,Xiue Ma,Yi Liu,Dandan Liang,Dan Shi,Honghui Ma,Li Li,Qi Zhang,Yihan Chen
标识
DOI:10.1038/s41467-022-31996-9
摘要
Abstract Kinase-catalyzed phosphorylation plays a crucial role in pathological cardiac hypertrophy. Here, we show that CDC-like kinase 4 (CLK4) is a critical regulator of cardiomyocyte hypertrophy and heart failure. Knockdown of Clk4 leads to pathological cardiomyocyte hypertrophy, while overexpression of Clk4 confers resistance to phenylephrine-induced cardiomyocyte hypertrophy. Cardiac-specific Clk4 -knockout mice manifest pathological myocardial hypertrophy with progressive left ventricular systolic dysfunction and heart dilation. Further investigation identifies nexilin (NEXN) as the direct substrate of CLK4, and overexpression of a phosphorylation-mimic mutant of NEXN is sufficient to reverse the hypertrophic growth of cardiomyocytes induced by Clk4 knockdown. Importantly, restoring phosphorylation of NEXN ameliorates myocardial hypertrophy in mice with cardiac-specific Clk4 deletion. We conclude that CLK4 regulates cardiac function through phosphorylation of NEXN, and its deficiency may lead to pathological cardiac hypertrophy. CLK4 is a potential intervention target for the prevention and treatment of heart failure.
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