Calpain-1 induces endoplasmic reticulum stress in promoting cardiomyocyte apoptosis following hypoxia/reoxygenation

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Zheng, Dong^1,2,3,6  Wang, Grace⁴  Li, Shuai^2,3,4  Fan, Guo-Chang⁵  Peng, Tianqing^1,2,3,4,6 

[1] Soochow Univ, Inst Biol & Med Sci, Suzhou 215123, Peoples R China

[2] Lawson Hlth Res Inst, Crit Illness Res, London, ON, Canada

[3] Univ Western Ontario, Dept Med, London, ON N6A 4G5, Canada

[4] Univ Western Ontario, Dept Pathol, London, ON N6A 4G5, Canada

[5] Univ Cincinnati, Dept Pharmacol & Cell Biophys, Coll Med, Cincinnati, OH 45267 USA

[6] Soochow Univ, Inst Cardiovasc Sci, Suzhou 215008, Peoples R China

关键词: Calpain;    ER stress;    JNK1/2;    Apoptosis;    Hypoxia/reoxygenation;   

DOI  :  10.1016/j.bbadis.2015.01.019

来源: Elsevier

【 摘 要 】

Both calpain activation and endoplasmic reticulum (ER) stress are implicated in ischemic heart injury. However, the role of calpain in ER stress remains largely elusive. This study investigated whether calpain activation causes ER stress, thereby mediating cardiomyocyte apoptosis in an in vitro model of hypoxia/re-oxygenation (H/R). In neonatal mouse cardiomyocytes and rat cardiomyocyte-like H9c2 cells, up-regulation of calpain-1 sufficiently induced ER stress, c-Jun N-terminal protein kinase1/2 UNK1/2) activation and apoptosis. Inhibition of ER stress or JNK1/2 prevented apoptosis induced by calpain-1. In an in vitro model of H/R-induced injury in cardiomyocytes, H/R was induced by a 24-hour hypoxia followed by a 24-hour re-oxygenation. H/R activated calpain-1, induced ER stress and JNK1/2 activation, and triggered apoptosis. Inhibition of calpain and ER stress blocked JNK1/2 activation and prevented H/R-induced apoptosis. Furthermore, blockade of JNK1/2 signaling inhibited apoptosis following H/R. The role of calpain in ER stress was also demonstrated in an in vivo model of ischemia/reperfusion using transgenic mice over-expressing calpastatin. In summary, calpain-1 induces ER stress and JNK1/2 activation, thereby mediating apoptosis in cardiomyocytes. Accordingly, inhibition of calpain prevents ER stress, JNK1/2 activation and apoptosis in H/R-induced cardiomyocytes. Thus, ER stress/JNK1/2 activation may represent an important mechanism linking calpain-1 to ischemic injury. (C) 2015 Elsevier B.V. All rights reserved.

【 授权许可】

Free