Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 48, Issue 9, Pages 1182-1187Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2010.01.038
Keywords
SERCA; Sodium-calcium exchanger; Cardiac myocyte; Oxidative stress; Reactive thiols; Free radicals
Funding
- NIH National Heart, Lung, and Blood Institute [HL-61639, HL-20612, HL-31607, N01-HV-28178]
- American Heart Association
- Swiss National Science Foundation [SCORE 3232B-111352, 3200B-111353]
- La Fondation pour la Recherche Medicale [SPE20051105207]
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Myocardial failure is associated with increased oxidative stress and abnormal excitation-contraction coupling characterized by depletion of sarcoplasmic reticulum (SR) Ca2+ stores and a reduction in Ca2+-transient amplitude. Little is known about the mechanisms whereby oxidative stress affects Ca2+ handling and contractile function; however, reactive thiols may be involved. We used an in vitro cardiomyocyte system to test the hypothesis that short-term oxidative stress induces SR Ca2+ depletion via redox-mediated regulation of sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) and the sodium-Ca2+ exchanger (NCX) and that this is associated with thiol oxidation. Adult rat ventricular myocytes paced at 5 Hz were superfused with H2O2 (100 mu M, 15 min). H2O2 caused a progressive decrease in cell shortening followed by diastolic arrest, which was associated with decreases in SR Ca2+ content, systolic [Ca2+](i), and Ca2+-transient amplitude, but no change in diastolic [Ca2+](i). H2O2 caused reciprocal effects on the activities of SERCA (decreased) and NCX (increased). Pretreatment with the NCX inhibitor KB-R7943 before H2O2 increased diastolic [Ca2+](i) and mimicked the effect of SERCA inhibition with thapsigargin. These functional effects were associated with oxidative modification of thiols on both SERCA and NCX. In conclusion, redox-mediated SR Ca2+ depletion involves reciprocal regulation of SERCA and NCX, possibly via direct oxidative modification of both proteins. (C) 2010 Elsevier Inc. All rights reserved.
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