Calpain‐2 protects against heat stress‐induced cardiomyocyte apoptosis and heart dysfunction by blocking p38 mitogen‐activated protein kinase activation

卡尔帕因 p38丝裂原活化蛋白激酶 细胞凋亡 热休克蛋白 热休克蛋白27 钙蛋白酶抑制剂 细胞生物学 蛋白激酶A 激酶 热休克蛋白70 生物 分子生物学 生物化学 基因
作者
Zhifeng Liu,Jing‐jing Ji,Zheng Dong,Lei Su,Tianqing Peng
出处
期刊:Journal of Cellular Physiology [Wiley]
卷期号:234 (7): 10761-10770 被引量:23
标识
DOI:10.1002/jcp.27750
摘要

Abstract Cardiovascular dysfunction is a common complication among heatstroke patients, but its underlying mechanism is unclear. This study was designed to investigate the role of calpain‐2 and its downstream signal pathway in heat stress‐induced cardiomyocyte apoptosis and heart dysfunction. In cultured primary mouse neonatal cardiomyocytes (MNCs), heat stress (43°C for 2 hr) induced a heat‐shock response, as indicated by upregulated heat‐shock protein 27 (HSP27) expression and cellular apoptosis, as indicated by increased caspase‐3 activity, DNA fragmentation and decreased cell viability. Meanwhile, heat stress decreased calpain activity, which was accompanied by downregulated calpain‐2 expression and increased phosphorylation of p38, extraceIIuIar signaI‐reguIated protein kinase (ERK1/2) and c‐Jun N‐terminaI kinase (JNK). Calpain‐2 overexpression abrogated heat stress‐induced apoptosis and phosphorylation of p38 and JNK, but not of ERK1/2. Blocking only p38 prevented heat stress‐induced apoptosis in MNCs. In cardiac‐specific calpain‐2 overexpressing transgenic mice, p38 phosphorylation and cardiomyocyte apoptosis were decreased in the heart tissue of heatstroke mice, as revealed by western blot and terminal deoxynucleotidyl transferase dUTP nick end labelling assays, respectively. M‐mode echocardiography also demonstrated that calpain‐2 overexpression significantly improved heatstroke‐induced decreases in ventricular end‐diastolic volume and cardiac output. In conclusion, our study suggests that heat stress reduces calpain‐2 expression, which then activates p38, leading to cardiomyocyte apoptosis and heart dysfunction.
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