Deficient ryanodine receptor S -nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes
| Autor: | Farideh Beigi, Adriana V. Treuer, Daniel R. Gonzalez, Joshua M. Hare |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
Nitric Oxide Synthase Type III Nitric Oxide Synthase Type II chemistry.chemical_element Mice Transgenic Nitric Oxide Synthase Type I Calcium Ryanodine receptor 2 Nitric oxide Tacrolimus Binding Proteins Mice chemistry.chemical_compound Diastole Internal medicine medicine Animals Myocyte Myocytes Cardiac Sulfhydryl Compounds Phosphorylation Calcium metabolism Multidisciplinary Ryanodine receptor Arrhythmias Cardiac Ryanodine Receptor Calcium Release Channel S-Nitrosylation Biological Sciences musculoskeletal system Sarcoplasmic Reticulum Endocrinology chemistry cardiovascular system Oxidation-Reduction Homeostasis |
| Zdroj: | Proceedings of the National Academy of Sciences. 104:20612-20617 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0706796104 |
| Popis: | Altered Ca 2+ 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 Ca 2+ homeostasis. Diastolic Ca 2+ levels are elevated in NOS1 −/− and NOS1/NOS3 −/− but not NOS3 −/− myocytes compared with wild-type (WT), suggesting diastolic Ca 2+ 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 Ca 2+ leak and a proarrhythmic phenotype. NOS1 dysregulation may be a proximate cause of key phenotypes associated with heart disease. |
| Databáze: | OpenAIRE |
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