Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 44, Pages 18186-18191Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1210565109
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Funding
- National Institutes of Health (NIH) [HL-054807, HL-084142, HL-100105, HL-075443, HL-095463, AI-080633]
- DARPA [N66001-10-C-2015]
- Heart Rhythm Society
- NIH National Research Service Award
- Department of Medicine Physician Scientist Pathway at the MetroHealth Campus of Case Western Reserve University
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Nitric oxide (NO) derived from the activity of neuronal nitric oxide synthase (NOS1) is involved in S-nitrosylation of key sarcoplasmic reticulum (SR) Ca2+ handling proteins. Deficient S-nitrosylation of the cardiac ryanodine receptor (RyR2) has a variable effect on SR Ca2+ leak/sparks in isolated myocytes, likely dependent on the underlying physiological state. It remains unknown, however, whether such molecular aberrancies are causally related to arrhythmogenesis in the intact heart. Here we show in the intact heart, reduced NOS1 activity increased Ca2+-mediated ventricular arrhythmias only in the setting of elevated myocardial [Ca2+](i). These arrhythmias arose from increased spontaneous SR Ca2+ release, resulting from a combination of decreased RyR2 S-nitrosylation (RyR2-SNO) and increased RyR2 oxidation (RyR-SOx) (i.e., increased reactive oxygen species (ROS) from xanthine oxidoreductase activity) and could be suppressed with xanthine oxidoreductase (XOR) inhibition (i.e., allopurinol) or nitric oxide donors (i.e., S-nitrosoglutathione, GSNO). Surprisingly, we found evidence of NOS1 down-regulation of RyR2 phosphorylation at the Ca2+/calmodulin-dependent protein kinase (CaMKII) site (S2814), suggesting molecular cross-talk between nitrosylation and phosphorylation of RyR2. Finally, we show that nitroso-redox imbalance due to decreased NOS1 activity sensitizes RyR2 to a severe arrhythmic phenotype by oxidative stress. Our findings suggest that nitroso-redox imbalance is an important mechanism of ventricular arrhythmias in the intact heart under disease conditions (i.e., elevated [Ca2+](i) and oxidative stress), and that therapies restoring nitroso-redox balance in the heart could prevent sudden arrhythmic death.
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