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.
Liu
Limin
L
Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Yan
Yun
Y
Zeng
Ming
M
Zhang
Jian
J
Hanes
Martha A
MA
Ahearn
Gregory
G
McMahon
Timothy J
TJ
Dickfeld
Timm
T
Marshall
Harvey E
HE
Que
Loretta G
LG
Stamler
Jonathan S
JS
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