3-(4-fluorophenylethylamino)-1-methyl-4-(2-methyl-1h-indol-3-yl)-1h-pyrrole-2-5-dione and Myocardial-Ischemia

Inhibition of glycogen synthase kinase 3β (GSK-3β) has been reported to be cardioprotective during stressful conditions.. 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.. 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.

Topics: Animals; beta Catenin; Cadherins; Chronic Disease; Coronary Circulation; Coronary Vessels; Diet, High-Fat; Disease Models, Animal; Forkhead Box Protein O1; gamma Catenin; Glycogen Synthase Kinase 3 beta; Heart; Indoles; Maleimides; Metabolic Syndrome; Myocardial Ischemia; Myocardium; Neovascularization, Physiologic; Proto-Oncogene Proteins c-akt; Superoxide Dismutase; Sus scrofa; Swine; Vascular Endothelial Growth Factor Receptor-1