• Brittany A Potz, Laura A Scrimgeour, Sharif A Sabe, Richard T Clements, Neel R Sodha, and Frank W Sellke.
• Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
• J. Thorac. Cardiovasc. Surg. 2018 Jun 1; 155 (6): 2492-2503.

ObjectivesGlycogen synthase kinase 3β (GSK-3β) inhibition has been reported to increase microvascular density and improve myocardial blood flow in a porcine model of chronic myocardial ischemia and metabolic syndrome. Inhibition of GSK-3β can also be cardioprotective by modulating fibrosis signaling and mitochondrial-induced apoptosis. We hypothesized GSK-3β inhibition would have a beneficial effect on myocardial fibrosis and oxidative stress in a porcine model of chronic myocardial ischemia and metabolic syndrome.MethodsPigs were fed a high fat diet for 4 weeks followed by placement of an ameroid constrictor to the left circumflex coronary artery. Three weeks later animals received either no drug or a GSK-3β inhibitor. The diets and placebo/GSK-3β inhibition were continued for an additional 5 weeks, the pigs were then euthanized, and the myocardial tissue was harvested. Collagen expression was analyzed via Picrosirius staining. Oxidative stress was analyzed via Oxyblot analysis. Protein expression was analyzed via Western blot.ResultsGSK-3β inhibition was associated with decreased collagen expression and oxidative stress in the ischemic and nonischemic myocardial tissue compared with control. There was a decrease in profibrotic proteins transforming growth factor-β, p-SMAD2/3, and matrix metalloproteinase-9, and in proapoptotic and oxidative stress proteins, apoptosis inducing factor, the cleaved caspase 3/caspase 3 protein ratio and phosphorylated myeloid cell leukemia sequence-1 in the GSK-3β inhibited group compared with the control.ConclusionsIn the setting of metabolic syndrome and chronic myocardial ischemia, inhibition of GSK-3β decreases collagen formation and oxidative stress in myocardial tissue. GSK-3β inhibition might be having this beneficial effect by downregulating transforming growth factor-β/SMAD2/3 signaling and decreasing mitochondrial induced cellular stress.Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

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