Nitric oxide regulates mitochondrial oxidative stress protection via the transcriptional coactivator PGC-1alpha

  • Borniquel S
  • Valle I
  • Cadenas S
 et al. 
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Abstract

Nitric oxide (NO) has both prooxidant and antioxidant activities in the endothelium; however, the molecular mechanisms involved are still a matter of controversy. PGC-1alpha [peroxisome proliferators-activated receptor (PPAR) gamma coactivator 1-alpha] induces the expression of several members of the mitochondrial reactive oxygen species (ROS) detoxification system. Here, we show that NO regulates this system through the modulation of PGC-1alpha expression. Short-term (24 h) treatment up-regulates it. Treatment with the NOS inhibitor l-NAME has the opposite effect. Down-regulation of PGC-1alpha by NO is mediated by protein kinase G (PKG). It is blocked by the soluble guanylate cyclase (sGC) inhibitor ODQ and the PKG inhibitor KT5823, and mimicked by the cGMP analog 8-Br-cGMP. Changes in PGC-1alpha expression are in all cases paralleled by corresponding variations in the mitochondrial ROS detoxification system. Cells that transiently overexpress PGC-1alpha from the cytomeglovirus (CMV) promoter respond poorly to NO donors. Analysis of tissues from eNOS(-/-) mice showed reduced levels of PGC-1alpha and the mitochondrial ROS detoxification system. These data suggest that NO can regulate the mitochondrial ROS detoxification system both positively and negatively through PGC-1alpha.

Author-supplied keywords

  • Animals
  • Aorta
  • Cattle
  • Cell Culture Techniques
  • Endothelium, Vascular/cytology/drug effects/*physi
  • Heat-Shock Proteins/drug effects/*genetics
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria/drug effects/*physiology
  • NG-Nitroarginine Methyl Ester/pharmacology
  • Nitric Oxide Donors/*pharmacology
  • Nitric Oxide/*pharmacology
  • Oxidative Stress/drug effects/*physiology
  • Oxygen Consumption/drug effects
  • Peroxisome Proliferator-Activated Receptor Gamma C
  • Polymerase Chain Reaction
  • Trans-Activators/drug effects/*genetics
  • Transcription Factors/drug effects/*genetics
  • Umbilical Veins

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Authors

  • S Borniquel

  • I Valle

  • S Cadenas

  • S Lamas

  • M Monsalve

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