Abstract 9100: Statin Inhibits Apoptosis of Vascular Smooth Muscle Cells in Atherogenic Plaque via eNOs/HIF-1α-Mediated IAP-2 Activation: Implication for Plaque Stability
Background: Vascular smooth muscle cell (VSMC) apoptosis occurs in many arterial conditions, including aneurysm and atherosclerotic lesion formation and plaque rupture. Statins attenuate such negative vessel remodeling, but the mechanism of their vasculoprotective action remains poorly understood.
Methods and Results: To examine the actions of statins in vascular response to injury, we employed a plaque disruption model in apolipoprotein E-deficient (ApoE−/−) mice (Sasaki et al. ATVB 2006;26:1304–9), which were treated with vehicle (0.5% carboxymethyl cellulose; CMC), low-dose pitavastatin (1 mg/kg daily; Pit-L), high-dose pitavastatin (10 mg/kg/day; Pit-H), or the nitric oxide synthase (NOS) inhibitor L-NAME (20 mg/kg daily; L-NAM), by oral gavage daily for 10 days. Pitavastatin stimulated production of endothelial NOS (eNOS), phospho-Akt (p-Akt), hypoxia-induced factor 1α (HIF-1α), and inhibitory apoptosis protein-2 (IAP-2) and suppressed caspase 3, p53, and Bax in atherosclerotic plaque of carotid arteries of ApoE−/− mice. Increased apoptosis and cathepsin S activation, as well as plaque disruption concomitant with enhanced NADPH oxidase-derived superoxide production in the plaque of carotid arteries, were inhibited by pitavastatin. eNOS inhibition by L-NAME abolished these benefits. Deficiency of cathepsin S reduces atherogenic lesion formation and plaque disruption in ApoE−/− mice, and deficiency of its endogenous inhibitor cystatin C enhances these changes. In vitro, apoptosis rates were lower in cultured aorta-derived VSMCs of ApoE−/− /cathepsin S−/− mice and higher in those of ApoE−/−/cystatin C−/− mice than in those of ApoE−/− mice.
Conclusions: In this mouse model, statins may enhance the anti-apoptotic actions of IAP-2, in part through stimulation of the eNOS/HIF-1α signaling pathway, thus likely increasing atherogenic plaque stability.
- © 2010 by American Heart Association, Inc.