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: Dong Zheng, Grace Wang, Shuai Li, Guo-Chang Fan, Tianqing Peng
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1852 Issue 5 Pg. 882-92 (May 2015) ISSN: 0006-3002 [Print] Netherlands
• PMID: 25660447 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Calcium-Binding Proteins
• calpastatin
• Mitogen-Activated Protein Kinase 9
• Mitogen-Activated Protein Kinase 8
• Calpain
• Oxygen

Topics

• Animals
• Animals, Newborn
• Apoptosis (physiology)
• Blotting, Western
• Calcium-Binding Proteins (genetics, metabolism)
• Calpain (genetics, metabolism)
• Cell Hypoxia
• Cell Line
• Cells, Cultured
• Endoplasmic Reticulum Stress (physiology)
• Enzyme Activation (drug effects)
• Humans
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitogen-Activated Protein Kinase 8 (metabolism)
• Mitogen-Activated Protein Kinase 9 (metabolism)
• Myocardial Reperfusion Injury (genetics, metabolism)
• Myocytes, Cardiac (cytology, drug effects, metabolism)
• Oxygen (pharmacology)
• RNA Interference
• Rats