title: Peroxisome proliferator-activated receptor γ coactivator-1α is a central negative regulator of vascular senescence.
abstract: OBJECTIVE
  Cellular senescence influences organismal aging and increases predisposition to age-related diseases, in particular cardiovascular disease, a leading cause of death and disability worldwide. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis and function, oxidative stress, and insulin resistance. Senescence is associated with telomere and mitochondrial dysfunction and oxidative stress, implying a potential causal role of PGC-1α in senescence pathogenesis.
  
  
  RESULTS
  We generated a PGC-1α(+/-)/apolipoprotein E(-/-) mouse model and showed that PGC-1α deficiency promotes a vascular senescence phenotype that is associated with increased oxidative stress, mitochondrial abnormalities, and reduced telomerase activity. PGC-1α disruption results in reduced expression of the longevity-related deacetylase sirtuin 1 (SIRT1) and the antioxidant catalase, and increased expression of the senescence marker p53 in aortas. Further, angiotensin II, a major hormonal inducer of vascular senescence, induces prolonged lysine acetylation of PGC-1α and releases the PGC-1α-FoxO1 complex from the SIRT1 promoter, thus reducing SIRT1 expression. The phosphorylation-defective mutant PGC-1α S570A is not acetylated, is constitutively active for forkhead box O1-dependent SIRT1 transcription, and prevents angiotensin II-induced senescence. Acetylation of PGC-1α by angiotensin II interrupts the PGC-1α-forkhead box O1-SIRT1 feed-forward signaling circuit leading to SIRT1 and catalase downregulation and vascular senescence.
  
  
  CONCLUSIONS
  PGC-1α is a primary negative regulator of vascular senescence. Moreover, the central role of posttranslational modification of PGC-1α in regulating angiotensin II-induced vascular senescence may inform development of novel therapeutic strategies for mitigating age-associated diseases, such as atherosclerosis.
authors: Division of Cardiology, Emory University Hospital, Emory University School of Medicine, Atlanta, GA, USA.
authors: Shiqin
authors: S
authors: Xiong
authors: Gloria
authors: G
authors: Salazar
authors: Nikolay
authors: N
authors: Patrushev
authors: Minhui
authors: M
authors: Ma
authors: Farshad
authors: F
authors: Forouzandeh
authors: Lula
authors: L
authors: Hilenski
authors: R Wayne
authors: RW
authors: Alexander
mesh_terms: D000107:Acetylation; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002374:Catalase / Q000032:analysis; D016922:Cellular Senescence; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000032:analysis / Q000235:genetics; D019098:Telomerase / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D014157:Transcription Factors; D000804:Angiotensin II; D002374:Catalase; D019098:Telomerase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1