Glycogen Synthase Kinase 3b Inhibition Improves Myocardial Angiogenesis and Perfusion in a Swine Model of Metabolic Syndrome

Background-—Inhibition of glycogen synthase kinase 3b (GSK-3b) has been reported to be cardioprotective during stressful conditions. Methods and Results-—Pigs were fed a high-fat diet for 4 weeks to develop metabolic syndrome, then underwent placement of an ameroid constrictor to their left circumflex artery to induce chronic myocardial ischemia. Two weeks later, animals received either: no drug (high cholesterol control group [HCC]) or a GSK-3b inhibitor (GSK-3b inhibited group [GSK-3bI]), which were continued for 5 weeks, followed by myocardial tissue harvest. Coronary blood flow and vessel density were significantly increased in the GSK-3bI group compared to the HCC group. Expression levels of the following proteins were greater in the GSK-3bI group compared to the HCC group: vascular endothelial growth factor receptor 1, vascular endothelial cadherin, c-catenin, b-catenin, protein kinase B, phosphorylated forkhead box O1, and superoxide dismutase 2. Conclusions-—In the setting of metabolic syndrome, inhibition of GSK-3b increases blood flow and vessel density in chronically ischemic myocardium. We identified several angiogenic, cell survival, and differentiation pathways that include b-catenin signaling and AKT/FOXO1, through which GSK-3b appears to improve vessel density and blood flow. These results may provide a potential mechanism for medical therapy of patients suffering from coronary artery disease and metabolic syndrome. ( J Am Heart Assoc. 2016;5:e003694 doi: 10.1161/JAHA.116.003694).