Proliferator Coactivator 1α Deletion Induces Angiotensin II–Associated Vascular Dysfunction by Increasing Mitochondrial Oxidative Stress and Vascular Inflammation
Objective—Peroxisome proliferator coactivator 1α (PGC-1α) is an important mediator of mitochondrial biogenesis and function. Because dysfunctional mitochondria might be involved in the pathogenesis of vascular disease, the current study was designed to investigate the effects of in vivo PGC-1α deficiency during chronic angiotensin II (ATII) treatment.
Approach and Results—Although ATII infusion at subpressor doses (0.1 mg/kg per day for 7 days) did not cause vascular dysfunction in wild-type mice, it led to impaired endothelial-dependent and endothelial-independent relaxation in PGC-1α knockout mice. In parallel, oxidative stress was increased in aortic rings from ATII-treated PGC-1α knockout mice, whereas no change in nitric oxide production was observed. By using the mitochondrial-specific superoxide dye MitoSox and complex I inhibitor rotenone, we identified the mitochondrial respiratory chain as the major PGC-1α–dependent reactive oxygen species source in vivo, accompanied by increased vascular inflammation and cell senescence. In vivo treatment with the mitochondria-targeted antioxidant Mito-TEMPO partially corrected endothelial dysfunction and prevented vascular inflammation in ATII-treated PGC-1α mice, suggesting a causative role of mitochondrial reactive oxygen species in this setting.
Conclusions—PGC-1α deletion induces vascular dysfunction and inflammation during chronic ATII infusion by increasing mitochondrial reactive oxygen species production.
- Received June 24, 2012.
- Accepted June 4, 2013.
- © 2013 American Heart Association, Inc.