Abstract 12907: Inhibition of FoxO1-SIRT1 Signaling by Sustained Acetylation of PGC-1 Alpha Promotes Angiotensin II-Induced Vascular Senescence
Angiotensin II (Ang II) is a major mediator of the renin-angiotensin system and enables aging-associated cardiovascular diseases such as atherosclerosis through angiotensin type 1 receptors (AT1Rs). AT1R deficiency promotes longevity in mice; the mechanisms are poorly understood. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a key negative regulator of aging-associated telomere and mitochondrial dysfunction, insulin resistance, and elevated oxidative stress, inferring its potential role in senescence pathogenesis. We posited that PGC-1α is an important regulator of Ang II-induced vascular senescence. We developed a PGC-1α+/-/ApoE-/- mouse model and show that PGC-1α deficiency (93%) results in enhanced (100%) susceptibility to Ang II-induced vascular senescence and concomitant reductions in SIRT1 (deacetylase for PGC-1α and FoxO1) and catalase expression (90% and 79%, respectively). We show that Ang II (100 nM) induces prolonged lysine acetylation of PGC-1α and releases the PGC-1α•FoxO1 transcriptional complex from the SIRT1 promoter, thus suppressing SIRT1 expression. SIRT1 reduction in turn promotes sustained acetylation of PGC-1α via a feedback loop mechanism. Moreover, overexpression of the acetylation defective mutant PGC-1α S570A coactivates FoxO1-dependent SIRT1 transcription and prevents Ang II-induced vascular smooth cell (VSMC) senescence through inhibition of FoxO1 phosphorylation. Consistently, PGC-1α depletion by siRNA accelerates Ang II-induced VSMC senescence. Our findings identify reversible prolonged acetylation of PGC-1α as an important molecular mechanism to fine-tune the positive feedback circuit of PGC-1α-FoxO1-SIRT1 signaling and unravel a novel function for PGC-1α as a negative regulator of vascular senescence. Modulation of PGC-1α acetylation may provide a viable therapeutic strategy in Ang II-dependent, aging-related cardiovascular diseases.
- © 2011 by American Heart Association, Inc.