Abstract 9958: Enabling of PGC-1 Alpha Signaling by Alpha-lipoic Acid Inhibits and Reverses Vascular Senescence

Abstract

Vascular senescence has been implicated in atherosclerotic arterial disease clinically and in animals. Senescence induction conditions include telomere and mitochondrial dysfunction, DNA damage, and elevated oxidative stress. Alpha-lipoic acid (ALA) is a powerful natural antioxidant, implying a potential important role of ALA in senescence pathogenesis. We showed recently peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a primary negative regulator of vascular senescence. We thus posited that ALA may inhibit vascular senescence via enabling PGC-1 alpha signaling networks. We generated a PGC-1 alpha and ApoE double knockout mouse model and show that mice with PGC-1 alpha deficiency develop a senescence phenotype (2.25 fold) that is associated with increased cellular general ROS levels (3 fold) and mitochondrial superoxide production (2 fold). We demonstrate that ALA (100 μM for in vitro, 10 mg/kg/d for in vivo experiments) upregulates expression of PGC-1 alpha and PGC-1 alpha-dependent downstream ROS defense molecules, including SIRT1, catalase, MnSOD, heme oxygenase 1 (HO-1), and its mitochondrial targets including NRF-1 and 2, and TFAM, while decreases expression of the senescence marker p53 in mice aortas and vascular smooth muscle cells (VSMC). The upregulation of the endogenous antioxidants and mitochondrial targets is prevented by PGC-1 alpha deficiency. Further, ALA (100 μM) is sufficient to inhibit and reverse VSMC senescence through a blockade of PGC-1 alpha acetylation, thus preventing the downregulation of SIRT1 and catalase triggered by angiotensin II (Ang II), a major hormonal inducer of vascular senescence. Moreover, ALA inhibits Ang II-induced cellular ROS and mitochondrial superoxide production, both of which are abolished in the absence of PGC-1 alpha. Our findings show that ALA is an important activator of PGC-1 alpha signaling pathways and unravel a previously unappreciated role for ALA in mitigating oxidative stress-dependent vascular senescence via PGC-1 alpha. These observations support the notion that enabling of PGC-1 alpha signaling network might be a promising strategy in the development of intervention for oxidative stress-dependent, age-related, chronic diseases.