Peroxisome proliferator-activated receptor ? coactivator-1? is a central negative regulator of vascular senescence.

ABSTRACT: 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 ? coactivator-1? (PGC-1?) 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-1? in senescence pathogenesis.We generated a PGC-1?(+/-)/apolipoprotein E(-/-) mouse model and showed that PGC-1? deficiency promotes a vascular senescence phenotype that is associated with increased oxidative stress, mitochondrial abnormalities, and reduced telomerase activity. PGC-1? 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-1? and releases the PGC-1?-FoxO1 complex from the SIRT1 promoter, thus reducing SIRT1 expression. The phosphorylation-defective mutant PGC-1? S570A is not acetylated, is constitutively active for forkhead box O1-dependent SIRT1 transcription, and prevents angiotensin II-induced senescence. Acetylation of PGC-1? by angiotensin II interrupts the PGC-1?-forkhead box O1-SIRT1 feed-forward signaling circuit leading to SIRT1 and catalase downregulation and vascular senescence.PGC-1? is a primary negative regulator of vascular senescence. Moreover, the central role of posttranslational modification of PGC-1? in regulating angiotensin II-induced vascular senescence may inform development of novel therapeutic strategies for mitigating age-associated diseases, such as atherosclerosis.

SUBMITTER: Xiong S 

PROVIDER: S-EPMC3663327 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature