Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 15, Pages 6297-6302Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0901043106
Keywords
angiogenesis; HIF-1 alpha; myocardial infarction; nitric oxide; S-nitrosylation
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Funding
- NHLBI NIH HHS [P01 HL075443, P01 HL075443-05, P01-HL075443] Funding Source: Medline
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Despite substantial evidence that nitric oxide (NO) and/or endogenous S-nitrosothiols (SNOs) exert protective effects in a variety of cardiovascular diseases, the molecular details are largely unknown. Here we show that following left coronary artery ligation, mice with a targeted deletion of the S-nitrosoglutathione reductase gene (GSNOR(-/-)) have reduced myocardial infarct size, preserved ventricular systolic and diastolic function, and maintained tissue oxygenation. These profound physiological effects are associated with increases in myocardial capillary density and S-nitrosylation of the transcription factor hypoxia inducible factor-1 alpha (HIF-1 alpha) under normoxic conditions. We further show that S-nitrosylated HIF-1 alpha binds to the vascular endothelial growth factor (VEGF) gene, thus identifying a role for GSNO in angiogenesis and myocardial protection. These results suggest innovative approaches to modulate angiogenesis and preserve cardiac function.
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