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Resveratrol Inhibits Neointimal Growth after Arterial Injury in High-Fat-Fed Rodents: The Roles of SIRT1 and AMPK
June Guo1, Troy J Pereira2, Yusaku Mori1,3
1Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Abstract:
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.
Insights
Resveratrol (RSV) reduces neointimal hyperplasia in high-fat-fed rats and mice, improving insulin sensitivity. This vasculoprotective effect is mediated by AMP-activated kinase (AMPK) rather than sirtuin 1 (SIRT1).
Area of Science:
- Cardiovascular Research
- Metabolic Syndrome
- Pharmacology
Background:
- Insulin and resveratrol (RSV) reduce neointimal hyperplasia via endothelial nitric oxide synthase (eNOS) activation in rodents.
- Insulin's vasculoprotective effect is lost in high-fat-fed, insulin-resistant rats.
- RSV activates eNOS independently of insulin signaling through sirtuin 1 (SIRT1) and AMP-activated kinase (AMPK).
Purpose of the Study:
- To determine if RSV retains its vasculoprotective effects in high-fat-fed, insulin-resistant rats.
- To investigate the roles of SIRT1 and AMPK in mediating RSV's effects on neointimal hyperplasia.
Main Methods:
- High-fat feeding was used to induce insulin resistance in rats.
- RSV treatment was administered to high-fat-fed rats and mice.
- Genetic mouse models (SIRT1 inactive/null, AMPKα2-null) were used to study the mechanisms of RSV action.
Main Results:
- High-fat feeding increased insulin resistance and neointimal area.
- RSV improved insulin sensitivity and reduced neointimal area in high-fat-fed rats (p < 0.05).
- RSV's effect was independent of SIRT1 but dependent on AMPKα2 in mice.
Conclusions:
- RSV demonstrates vasculoprotective effects against neointimal hyperplasia in high-fat-fed conditions.
- The mechanism of RSV's action involves AMPK activation, not SIRT1.
- RSV may be a therapeutic candidate for preventing vascular complications associated with metabolic syndrome.
