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

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-1α [peroxisome proliferators-activated receptor (PPAR) γ coactivator 1-α] 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-1α expression. Short-term (<12 h) treatment of endothelial cells with NO donors down-regulates PGC-1α expression, whereas long-term (>24 h) treatment up-regulates it. Treatment with the NOS inhibitor L-NAME has the opposite effect. Downregulation of PGC-1α 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-1α expression are in all cases paralleled by corresponding variations in the mitochondrial ROS detoxification system. Cells that transiently overexpress PGC-1α from the cytomeglovirus (CMV) promoter respond poorly to NO donors. Analysis of tissues from eNOS-/- mice showed reduced levels of PGC-1α and the mitochondrial ROS detoxification system. These data suggest that NO can regulate the mitochondrial ROS detoxification system both positively and negatively through PGC-1α.