Short Communication: Oxidative Posttranslational Modifications Mediate Decreased SERCA Activity and Myocyte Dysfunction in Gαq-Overexpressing Mice

Abstract

Background: Myocyte contractile dysfunction occurs in pathological remodeling in association with abnormalities in calcium regulation. Mice with cardiac myocyte–specific overexpression of Gαq develop progressive left ventricular failure associated with myocyte contractile dysfunction and calcium dysregulation. Objective: We tested the hypothesis that myocyte contractile dysfunction in the Gαq mouse heart is mediated by reactive oxygen species, and in particular, oxidative posttranslational modifications, which impair the function of sarcoplasmic reticulum Ca²⁺-ATPase (SERCA). Methods and Results: Freshly isolated ventricular myocytes from Gαq mice had marked abnormalities of myocyte contractile function and calcium transients. In Gαq myocardium, SERCA protein was not altered in quantity but displayed evidence of oxidative cysteine modifications reflected by decreased biotinylated iodoacetamide labeling and evidence of specific irreversible oxidative modifications consisting of sulfonylation at cysteine 674 and nitration at tyrosines 294/295. Maximal calcium-stimulated SERCA activity was decreased 47% in Gαq myocardium. Cross-breeding Gαq mice with transgenic mice that have cardiac myocyte-specific overexpression of catalase (a) decreased SERCA oxidative cysteine modifications, (b) decreased SERCA cysteine 674 sulfonylation and tyrosine 294/295 nitration, (c) restored SERCA activity, and (d) improved myocyte calcium transients and contractile function. Conclusions: In Gαq-induced cardiomyopathy, myocyte contractile dysfunction is mediated, at least in part, by 1 or more oxidative posttranslational modifications of SERCA. Protein oxidative posttranslational modifications contribute to the pathophysiology of myocardial dysfunction and thus may provide a target for therapeutic intervention.