Essential Roles of S-nitrosothiols in Vascular Homeostasis and Endotoxic Shock

Cell. 2004 Feb 20;116(4):617-28. doi: 10.1016/s0092-8674(04)00131-x.

Abstract

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.

MeSH terms

  • Alcohol Dehydrogenase
  • Alleles
  • Animals
  • Blood Pressure
  • Blood Vessels / physiology*
  • Cysteine / chemistry
  • Endotoxins
  • Erythrocytes / metabolism
  • Exons
  • Female
  • Gene Deletion
  • Genetic Vectors
  • Glutathione Reductase / genetics*
  • Heterozygote
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Chemical
  • Models, Genetic
  • NADH, NADPH Oxidoreductases / metabolism
  • Nitric Oxide / metabolism
  • Phenotype
  • S-Nitrosoglutathione / metabolism
  • S-Nitrosothiols / metabolism*
  • Shock
  • Shock, Septic / metabolism*
  • Sulfhydryl Compounds
  • Time Factors

Substances

  • Endotoxins
  • S-Nitrosothiols
  • Sulfhydryl Compounds
  • Nitric Oxide
  • S-Nitrosoglutathione
  • Adh5 protein, mouse
  • Alcohol Dehydrogenase
  • NADH, NADPH Oxidoreductases
  • Glutathione Reductase
  • Cysteine