Peroxisome proliferator coactivator 1a (PGC‐1a) deficiency accelerates endothelial dysfunction during chronic angiotensin II treatment by increasing mitochondrial oxidative stress and vascular aging

Abstract

ObjectivePGC‐1a is an important mediator of mitochondrial biogenesis and function. We have previously shown that the AMP‐activated protein kinase (AMPK) protects endothelial cells against oxidative stress by preservation of mitochondrial function in a PGC‐1a dependent manner. Since dysfunctional mitochondria might be involved in the pathogenesis of vascular disease, we investigated the effects of in vivo PGC‐1a deficiency during chronic angiotensin II (ATII) treatment.Methods and ResultsDeletion of PGC‐1a had no effect on endothelial function or mitochondrial mass in aortic tissue under basal conditions. However, chronic ATII infusion resulted in mild endothelial dysfunction, which was significantly impaired in PGC‐ 1a knockout mice. In parallel, oxidative stress was increased in aortic rings from ATII‐treated PGC‐1a knockout mice while serum antioxidative capacity was decreased. By using the mitochondrial specific superoxide dye mitoSOX and complex I inhibitor rotenone, we identified the mitochondrial respiratory chain as the major PGC‐1a dependent ROS source in vivo. In accordance with the prominent role of mitochondrial ROS for the signalling events leading to vascular aging and apoptosis, we found increased expression of p16INK4 and Chk‐2 as markers of cell senescence as well as increased TUNEL‐staining accompanied by activation of the JNK pathway in aortas from ATII treated PGC‐1a knockout mice.ConclusionsPGC‐1a deficiency impairs endothelial function during chronic ATII infusion by increasing mitochondrial ROS production, resulting in premature vascular aging and apoptosis.