| First Author | Xiong S | Year | 2013 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 33 |
| Issue | 5 | Pages | 988-98 |
| PubMed ID | 23430617 | Mgi Jnum | J:217966 |
| Mgi Id | MGI:5616289 | Doi | 10.1161/ATVBAHA.112.301019 |
| Citation | Xiong S, et al. (2013) Peroxisome proliferator-activated receptor gamma coactivator-1alpha is a central negative regulator of vascular senescence. Arterioscler Thromb Vasc Biol 33(5):988-98 |
| abstractText | 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 gamma coactivator-1alpha (PGC-1alpha) 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-1alpha in senescence pathogenesis. APPROACH AND RESULTS: We generated a PGC-1alpha(+/-)/apolipoprotein E(-/-) mouse model and showed that PGC-1alpha deficiency promotes a vascular senescence phenotype that is associated with increased oxidative stress, mitochondrial abnormalities, and reduced telomerase activity. PGC-1alpha 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-1alpha and releases the PGC-1alpha-FoxO1 complex from the SIRT1 promoter, thus reducing SIRT1 expression. The phosphorylation-defective mutant PGC-1alpha S570A is not acetylated, is constitutively active for forkhead box O1-dependent SIRT1 transcription, and prevents angiotensin II-induced senescence. Acetylation of PGC-1alpha by angiotensin II interrupts the PGC-1alpha-forkhead box O1-SIRT1 feed-forward signaling circuit leading to SIRT1 and catalase downregulation and vascular senescence. CONCLUSIONS: PGC-1alpha is a primary negative regulator of vascular senescence. Moreover, the central role of posttranslational modification of PGC-1alpha in regulating angiotensin II-induced vascular senescence may inform development of novel therapeutic strategies for mitigating age-associated diseases, such as atherosclerosis. |
