Deficient ryanodine receptor S-nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes

Daniel R. Gonzalez, Farideh Beigi, Adriana V. Treuer, Joshua M. Hare

Research output: Contribution to journalArticle

143 Scopus citations

Abstract

Altered Ca2+ homeostasis is a salient feature of heart disease, where the calcium release channel ryanodine receptor (RyR) plays a major role. Accumulating data support the notion that neuronal nitric oxide synthase (NOS1) regulates the cardiac RyR via S-nitrosylation. We tested the hypothesis that NOS1 deficiency impairs RyR S-nitrosylation, leading to altered Ca2+ homeostasis. Diastolic Ca2+ levels are elevated in NOS1-/- and NOS1/NOS3-/- but not NOS3-/- myocytes compared with wild-type (WT), suggesting diastolic Ca2+ leakage. Measured leak was increased in NOS1-/- and NOS1/NOS3-/- but not in NOS3 -/- myocytes compared with WT. Importantly, NOS1-/- and NOS1/NOS3-/- myocytes also exhibited spontaneous calcium waves. Whereas the stoichiometry and binding of FK-binding protein 12.6 to RyR and the degree of RyR phosphorylation were not altered in NOS1-/- hearts, RyR2 S-nitrosylation was substantially decreased, and the level of thiol oxidation increased. Together, these findings demonstrate that NOS1 deficiency causes RyR2 hyponitrosylation, leading to diastolic Ca2+ leak and a proarrhythmic phenotype. NOS1 dysregulation may be a proximate cause of key phenotypes associated with heart disease.

Original languageEnglish (US)
Pages (from-to)20612-20617
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number51
DOIs
StatePublished - Dec 18 2007

Keywords

  • Excitation-contraction coupling
  • Heart
  • Heart failure
  • Nitric oxide
  • Oxidative stress

ASJC Scopus subject areas

  • Genetics
  • General

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