Endogenous S-nitrosothiols protect against myocardial injury.
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-1alpha (HIF-1alpha) under normoxic conditions. We further show that S-nitrosylated HIF-1alpha 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.
Lima
Brian
B
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Lam
Gregory K W
GK
Xie
Liang
L
Diesen
Diana L
DL
Villamizar
Nestor
N
Nienaber
Jeffrey
J
Messina
Emily
E
Bowles
Dawn
D
Kontos
Christopher D
CD
Hare
Joshua M
JM
Stamler
Jonathan S
JS
Rockman
Howard A
HA