The rates of restenosis after percutaneous transluminal angioplasty are higher in diabetic than nondiabetic patients. Insulin is protective against restenosis, but these effects are diminished in the case of insulin resistance, which develops with high fat diet (HFD). Therefore, it makes sense to use an insulin-sensitizing compound which also has vasculoprotective effects such as resveratrol. Resveratrol is a phenolic compound found in plant tissues such as the skin of grapes, and has been hypothesized to account for the lower rates of cardiovascular disease among countries with high wine consumption. We have shown that resveratrol decreases neointimal formation in both mouse and rat models of arterial injury, and also that these effects are exerted through eNOS (endothelial nitric oxide synthase). We hypothesized that resveratrol acts though Sirt1, a NAD+-dependent deacetylase, to activate eNOS and decrease neointimal formation, but did not see any difference between neointimal growth of control and Sirt1-/- mice given HFD. AMPK (AMP-activated protein kinase) is an energy sensor which also protects against neointimal hyperplasia in the vasculature via directly activating eNOS and inhibiting the migration of vascular smooth muscle cells. Knocking out the α2 subunit of AMPK in particular has been shown to increase neointimal growth in mouse carotid artery in response to injury. We investigated the effect of resveratrol on neointimal growth after femoral arterial injury of wild type and AMPKα2 knock-out mice given HFD. Resveratrol was given at 0.0375% in the diet two days after wire injury. After 28 days, arteries were harvested and histomorphometric analysis was performed on the cross-sections. We found that neointimal growth was significantly higher in AMPKα2 knock-out mice given resveratrol compared to wild type mice given resveratrol (p<0.05). These results suggest that the vasculoprotective effects of resveratrol are mediated through AMPK.
L. Zhou: None. J. Guo: None. H. Zhang: None. S. Heximer: None. A. Giacca: None.