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

BACKGROUND: Inhibition of glycogen synthase kinase 3β (GSK‐3β) 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‐3β inhibitor (GSK‐3β inhibited group [GSK‐3βI]), which were continued for 5 weeks, followed by myocardial tissue harvest. Coronary blood flow and vessel density were significantly increased in the GSK‐3βI group compared to the HCC group. Expression levels of the following proteins were greater in the GSK‐3βI group compared to the HCC group: vascular endothelial growth factor receptor 1 , vascular endothelial cadherin, γ‐catenin, β‐catenin, protein kinase B, phosphorylated forkhead box O1, and superoxide dismutase 2. CONCLUSIONS: In the setting of metabolic syndrome, inhibition of GSK‐3β increases blood flow and vessel density in chronically ischemic myocardium. We identified several angiogenic, cell survival, and differentiation pathways that include β‐catenin signaling and AKT/FOXO1, through which GSK‐3β 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.