title: Peroxisome proliferator-activated receptor γ, coactivator 1α deletion induces angiotensin II-associated vascular dysfunction by increasing mitochondrial oxidative stress and vascular inflammation.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor γ, 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.
  
  
  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.
authors.affiliation: Department of Cardiology, II. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Germany.
authors.forename: Swenja
authors.initials: S
authors.lastname: Kröller-Schön
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansen
authors.forename: Andrea
authors.initials: A
authors.lastname: Schüler
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Michael
authors.initials: M
authors.lastname: Hausding
authors.forename: Jasmin Ghaemi
authors.initials: JG
authors.lastname: Kerahrodi
authors.forename: Maike
authors.initials: M
authors.lastname: Beisele
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Lackner
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors; D014657:Vasculitis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D014157:Transcription Factors; D014662:Vasoconstrictor Agents; D000804:Angiotensin II
keywords: endothelium; inflammation; mitochondria; oxidative stress