Impaired S-nitrosylation of the ryanodine receptor caused by xanthine oxidase activity contributes to calcium leak in heart failure

Daniel R. Gonzalez, Adriana V. Treuer, Jorge Castellanos, Raul A. Dulce, Joshua Hare

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

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 Ca2+ 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 Ca2+ leak, improving Ca2+ handling and contractility. Together these findings demonstrate that nitroso-redox imbalance causes RyR2 oxidation, hyponitrosylation, and SR Ca2+ leak, a hallmark of cardiac dysfunction. The reversal of this phenotype by inhibition of xanthine oxidase has important pathophysiologic and therapeutic implications.

Original languageEnglish
Pages (from-to)28938-28945
Number of pages8
JournalJournal of Biological Chemistry
Volume285
Issue number37
DOIs
StatePublished - Sep 10 2010

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Ryanodine Receptor Calcium Release Channel
Xanthine Oxidase
Heart Failure
Calcium
Sarcoplasmic Reticulum
Oxidation-Reduction
Excitation Contraction Coupling
Rats
Inbred WKY Rats
Dilated Cardiomyopathy
Post Translational Protein Processing
Superoxides
Muscle Cells
Muscle
Skeletal Muscle
Phenotype
Oxidation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Impaired S-nitrosylation of the ryanodine receptor caused by xanthine oxidase activity contributes to calcium leak in heart failure. / Gonzalez, Daniel R.; Treuer, Adriana V.; Castellanos, Jorge; Dulce, Raul A.; Hare, Joshua.

In: Journal of Biological Chemistry, Vol. 285, No. 37, 10.09.2010, p. 28938-28945.

Research output: Contribution to journalArticle

Gonzalez, Daniel R. ; Treuer, Adriana V. ; Castellanos, Jorge ; Dulce, Raul A. ; Hare, Joshua. / Impaired S-nitrosylation of the ryanodine receptor caused by xanthine oxidase activity contributes to calcium leak in heart failure. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 37. pp. 28938-28945.
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