Abstract 601: Mechanistic Dichotomy Of Resveratrol-mediated Inhibition Of Vascular Smooth Muscle Cell Proliferation And Restenosis
Angioplasty is a widely used therapy for coronary artery stenosis, but its application is limited by restenosis occuring in 30 – 40% of patients within 3– 6 months of surgery. Restenosis is due to intimal hyperplasia resulting from migration to and proliferation of vascular smooth muscle cells (VSMC) within the intima. Recent epidemiological evidence suggests red wine exerts greater cardioprotection in women than men. Our hypothesis was that the anti-proliferative effects of resveratrol are mediated by estrogen receptor stimulation. We thus determined effects of resveratrol in VSMC isolated from female rats, compared to female VSMC treated with siRNA for estrogen receptor- (ER-)α. At low doses (0.5–25 μM) resveratrol inhibited VSMC proliferation through an ER-α dependent increase in inducible nitric oxide synthase (iNOS) activity and inhibited the cells in S phase, but at high doses (50–100 μM) the mechanism was NF-κB dependent, with inhibition of cells in G0/G1 phase. At all doses, resveratrol inhibited IKK activity, an upstream kinase for NF-κB activation, but its effect at low doses was partially reversed by ER-α blockade. We also found a mechanistic link between ER-α receptors, cyclooxygenase-2 (COX-2), a known modulator of VSMC proliferation, and resveratrol. At low doses, resveratrol induced COX-2 expression, consistent with ER-α stimulation, while at high doses it inhibited COX-2 protein levels, likely due to an inhibition of NF-kB. To confirm these findings in an in vivo model for restenosis, B6.129 (n=8 per group) mice were fed with a high fat diet +/− 50 mg/kg resveratrol for 2 weeks. A carotid artery endothelial denudation procedure was conducted and after recovery, the mice were again fed a high fat diet +/−resveratrol for 2 weeks. Resveratrol increased arterial iNOS activity (p<0.05) and total NO production (p<0.05) but inhibited NF-κB activation (p<0.01). Studies in progress utilizing ER-α (−/−) mice are determining the role of ER-α in resveratrol- mediated effects and whether resveratrol prevents neointimal hyperplasia in this model. In conclusion, though resveratrol clearly inhibited NF-κB activation, it appears that it’s predominate therapeutic effect at low pharmacologically relevant concentrations is via ERα modulation.