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Author Notes:

Address correspondence to: R. Wayne Alexander, MD, PhD, Division of Cardiology, Emory University Hospital, Suite H-153, 1364 Clifton Rd, NE, Atlanta, GA 30322, USA. Phone: 404-727-1749; Fax: (404) 727-3099; ralexan@emory.edu

We are grateful to Dr. Zolt Arany for providing PGC-1α knockout mice, Dr. J.A. Hill for AdFoxO1 (WT) and CA mutant, and Dr. Daniel P. Kelly for PGC-1α antibody.

No conflicts of interest exist.

Subjects:

Research Funding:

This work was funded by grants from NIH UO1 HL80711 and NIH HL60728.

Keywords:

  • Vascular senescence
  • PGC-1α
  • Angiotensin II
  • Signal transduction

PGC-1? Is a Central Negative Regulator of Vascular Senescence

Tools:

Journal Title:

Arteriosclerosis, Thrombosis, and Vascular Biology

Volume:

Volume 33, Number 5

Publisher:

, Pages 988-998

Type of Work:

Article | Post-print: After Peer Review

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. 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, inferring a potential causal role of PGC-1α in senescence pathogenesis. Methods and Results We generated a PGC-1α+/−/ApoE−/− mouse model and show 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 (Ang 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 FoxO1-dependent SIRT1 transcription and prevents Ang II-induced senescence. Acetylation of PGC-1α by Ang II interrupts the PGC-1α-FoxO1-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 post-translational modification of PGC-1α in regulating Ang II-induced vascular senescence may inform development of novel therapeutic strategies for mitigating age-associated diseases such as atherosclerosis.

Copyright information:

© 2013, Wolters Kluwer Health

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