Calreticulin (CRT), a Ca2+-binding molecular chaperone in the endoplasmic reticulum, plays a vital role in cardiac physiology and pathology. Oxidative stress is a main cause of myocardiac disorder in the ischemic heart, but the function of CRT under oxidative stress is not fully understood. In this study, the effect of overexpression of CRT on sarcoplasmic/endoplasmic reticulum Ca2+- ATPase (SERCA) 2a under oxidative stress was examined using myocardiac H9c2 cells transfected. with the CRT gene. The in vitro activity of SERCA2a and uptake of Ca-45(2+) into isolated microsomes were suppressed by H2O2 in CRT-overexpressing cells compared with controls. Moreover, SERCA2a protein was degraded via a proteasome-dependent pathway following the formation of a complex with CRT under the stress with H2O2. Thus, we conclude that overexpression of CRT enhances the inactivation and degradation of SERCA2a in the cells under oxidative stress, suggesting some pathophysiological functions of CRT in Ca2+ homeostasis of myocardiac disease. (c) 2005 Elsevier Inc. All rights reserved.