Open AccessGlycogen Synthase Kinase 3β Inhibition Improves Myocardial Angiogenesis and Perfusion in a Swine Model of Metabolic Syndrome
Author(s) -
Potz Brittany A.,
Sabe Ashraf A.,
Elmadhun Nassrene Y.,
Clements Richard T.,
Robich Michael P.,
Sodha Neel R.,
Sellke Frank W.
Publication year - 2016
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.116.003694
Subject(s) - medicine , gsk 3 , angiogenesis , glycogen synthase , endocrinology , protein kinase b , coronary artery disease , metabolic syndrome , gsk3b , vascular endothelial growth factor , cardiology , glycogen , kinase , signal transduction , biochemistry , biology , diabetes mellitus , vegf receptors
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.