S-Nitrosylation is a ubiquitous post-translational modification that regulates diverse
biologic processes. In skeletal muscle, hypernitrosylation of the
ryanodine receptor (RyR) causes sarcoplasmic reticulum (SR)
calcium leak, but whether abnormalities of cardiac RyR nitrosylation contribute to dysfunction of cardiac excitation-contraction coupling remains controversial. In this study, we tested the hypothesis that cardiac
RyR2 is hyponitrosylated in
heart failure, because of nitroso-redox imbalance. We evaluated excitation-contraction coupling and nitroso-redox balance in spontaneously hypertensive
heart failure rats with
dilated cardiomyopathy and age-matched Wistar-Kyoto rats. Spontaneously hypertensive
heart failure myocytes were characterized by depressed contractility, increased diastolic Ca(2+) leak, hyponitrosylation of
RyR2, and enhanced
xanthine oxidase derived
superoxide. Global S-nitrosylation was decreased in failing hearts compared with nonfailing.
Xanthine oxidase inhibition restored global and
RyR2 nitrosylation and reversed the diastolic SR Ca(2+) leak, improving Ca(2+) handling and contractility. Together these findings demonstrate that nitroso-redox imbalance causes
RyR2 oxidation, hyponitrosylation, and SR Ca(2+) leak, a hallmark of cardiac dysfunction. The reversal of this phenotype by inhibition of
xanthine oxidase has important pathophysiologic and therapeutic implications.