June Guo a , Troy J. Pereira b , Yusaku Mori a , c , Marel Gonzalez Medina a , Danna M. Breen a , Prasad S. Dalvi a , d , Hangjun Zhang a , Declan F. McCole e , Michael W. McBurney f , Scott P. Heximer a , Evangelia L. Tsiani g , h , Vernon W. Dolinsky b , Adria Giacca a , i , j , k , *
10 August 2020
We have shown that both insulin and resveratrol (RSV) decrease neointimal hyperplasia in chow-fed rodents via mechanisms that are in part overlapping and involve the activation of endothelial nitric oxide synthase (eNOS). However, this vasculoprotective effect of insulin is abolished in high-fat-fed insulin-resistant rats. Since RSV, in addition to increasing insulin sensitivity, can activate eNOS via pathways that are independent of insulin signaling, such as the activation of sirtuin 1 (SIRT1) and AMP-activated kinase (AMPK), we speculated that unlike insulin, the vasculoprotective effect of RSV would be retained in high-fat-fed rats. We found that high-fat feeding decreased insulin sensitivity and increased neointimal area and that RSV improved insulin sensitivity ( p < 0.05) and decreased neointimal area in high-fat-fed rats ( p < 0.05). We investigated the role of SIRT1 in the effect of RSV using two genetic mouse models. We found that RSV decreased neointimal area in high-fat-fed wild-type mice ( p < 0.05), an effect that was retained in mice with catalytically inactive SIRT1 ( p < 0.05) and in heterozygous SIRT1-null mice. In contrast, the effect of RSV was abolished in AMKPα2-null mice. Thus, RSV decreased neointimal hyperplasia after arterial injury in both high-fat-fed rats and mice, an effect likely not mediated by SIRT1 but by AMPKα2.