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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

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

Xiong Shiqin S Salazar Gloria G Patrushev Nikolay N Ma Minhui M Forouzandeh Farshad F Hilenski Lula L Alexander R Wayne RW

Arteriosclerosis, thrombosis, and vascular biology 20130221 5

<h4>Objective</h4>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 caus ...[more]

PMID: 23430617

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Project description:Peroxisome proliferator-activated receptor-? (PPAR?) plays an important role in the vasculature; however, the role of PPAR? in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPAR? in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPAR?-mediated signaling pathways that may prevent the development of AAA.We determined whether periaortic application of CaCl(2) renders vascular SMC-selective PPAR? knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.There is evidence of increased vessel dilatation in the abdominal aorta 6 weeks after 0.25M periaortic CaCl(2) application in SMPG KO mice compared with littermate controls (1.4 ± 0.3 mm [n = 8] vs 1.1 ± 0.2 mm [n = 7]; P = .000119). Results from SMPG KO mice indicate medial layer elastin degradation was greater 6 weeks after abluminal application of CaCl(2) to the abdominal aorta (P < .01). Activated cathepsin S, a potent elastin-degrading enzyme, was increased in SMPG KO mice vs wild-type controls. To further identify a role of PPAR? signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPAR? overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPAR? bound to a peroxisome proliferator-activated receptor response element (PPRE) -141 to -159 bp upstream of the cathepsin S gene sequence in mouse aortic SMCs. Also, adenoviral-mediated PPAR? overexpression and knockdown in cultured rat aortic SMCs decreases (P = .013) and increases (P = .018) expression of activated cathepsin S. Finally, immunohistochemistry demonstrated a greater inflammatory infiltrate in SMPG KO mouse aortas, as evidenced by elevations in F4/80 and tumor necrosis factor-? expression.In this study, we identify PPAR? as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPAR? in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPAR? activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.

Dataset Information

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

Publications

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

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