Impaired S-nitrosylation of the ryanodine receptor caused by xanthine oxidase activity contributes to calcium leak in heart failure.
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.
Gonzalez
Daniel R
DR
Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
Treuer
Adriana V
AV
Castellanos
Jorge
J
Dulce
Raul A
RA
Hare
Joshua M
JM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D010084:Oxidation-Reduction; D011499:Protein Processing, Post-Translational; D051381:Rats; D011921:Rats, Inbred WKY; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism*
D019837:Ryanodine Receptor Calcium Release Channel; D013481:Superoxides; D014969:Xanthine Oxidase; D002118:Calcium