Essential roles of S-nitrosothiols in vascular homeostasis and endotoxic shock.
The current perspective of NO biology is formulated predominantly from studies of NO synthesis. The role of S-nitrosothiol (SNO) formation and turnover in governing NO-related bioactivity remains uncertain. We generated mice with a targeted gene deletion of S-nitrosoglutathione reductase (GSNOR), and show that they exhibit substantial increases in whole-cell S-nitrosylation, tissue damage, and mortality following endotoxic or bacterial challenge. Further, GSNOR(-/-) mice have increased basal levels of SNOs in red blood cells and are hypotensive under anesthesia. Thus, SNOs regulate innate immune and vascular function, and are cleared actively to ameliorate nitrosative stress. Nitrosylation of cysteine thiols is a critical mechanism of NO function in both health and disease.
Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Limin
L
Liu
Yun
Y
Yan
Ming
M
Zeng
Jian
J
Zhang
Martha A
MA
Hanes
Gregory
G
Ahearn
Timothy J
TJ
McMahon
Timm
T
Dickfeld
Harvey E
HE
Marshall
Loretta G
LG
Que
Jonathan S
JS
Stamler
D000426:Alcohol Dehydrogenase; D000483:Alleles; D000818:Animals; D001794:Blood Pressure; D001808:Blood Vessels / Q000502:physiology*; D003545:Cysteine / Q000737:chemistry; D004731:Endotoxins; D004912:Erythrocytes / Q000378:metabolism; D005091:Exons; D005260:Female; D017353:Gene Deletion; D005822:Genetic Vectors; D005980:Glutathione Reductase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008956:Models, Chemical; D008957:Models, Genetic; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010641:Phenotype; D026422:S-Nitrosoglutathione / Q000378:metabolism; D026403:S-Nitrosothiols / Q000378:metabolism*; D012769:Shock; D012772:Shock, Septic / Q000378:metabolism*; D013438:Sulfhydryl Compounds; D013997:Time Factors
D004731:Endotoxins; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; C483598:Adh5 protein, mouse; D000426:Alcohol Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D005980:Glutathione Reductase; D003545:Cysteine