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 language | English (US) |
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Pages (from-to) | 20612-20617 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 104 |
Issue number | 51 |
DOIs | |
State | Published - Dec 18 2007 |
Externally published | Yes |
Keywords
- Excitation-contraction coupling
- Heart
- Heart failure
- Nitric oxide
- Oxidative stress
ASJC Scopus subject areas
- Genetics
- General