title: Calpain-1 induces endoplasmic reticulum stress in promoting cardiomyocyte apoptosis following hypoxia/reoxygenation.
abstract: 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 (JNK1/2) 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.
authors: Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, China; Critical Illness Research, Lawson Health Research Institute, Canada; Department of Medicine, University of Western Ontario, London, Ontario N6A 4G5, Canada; Institute of Cardiovascular Science, Soochow University, Suzhou 215008, China.
authors: Dong
authors: D
authors: Zheng
authors: Department of Pathology, University of Western Ontario, London, Ontario N6A 4G5, Canada.
authors: Grace
authors: G
authors: Wang
authors: Critical Illness Research, Lawson Health Research Institute, Canada; Department of Medicine, University of Western Ontario, London, Ontario N6A 4G5, Canada; Department of Pathology, University of Western Ontario, London, Ontario N6A 4G5, Canada.
authors: Shuai
authors: S
authors: Li
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati 45267, OH, USA.
authors: Guo-Chang
authors: GC
authors: Fan
authors: Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, China; Critical Illness Research, Lawson Health Research Institute, Canada; Department of Medicine, University of Western Ontario, London, Ontario N6A 4G5, Canada; Department of Pathology, University of Western Ontario, London, Ontario N6A 4G5, Canada; Institute of Cardiovascular Science, Soochow University, Suzhou 215008, China. Electronic address: tpeng2@uwo.ca.
authors: Tianqing
authors: T
authors: Peng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats
chemical_list: D002135:Calcium-Binding Proteins; C033668:calpastatin; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D002154:Calpain; D010100:Oxygen
keywords: Apoptosis; Calpain; ER stress; Hypoxia/reoxygenation; JNK1/2