Glycogen Synthase Kinase 3β Inhibition Reduces Mitochondrial Oxidative Stress in Chronic Myocardial Ischemia

Journal of Thoracic and Cardiovascular Surgery

5 years ago

Glycogen Synthase Kinase 3β Inhibition Reduces Mitochondrial Oxidative Stress in Chronic Myocardial Ischemia

Glycogen synthase kinase 3β (GSK-3β) inhibition has been found 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 cardio protective 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.

Methods

Pigs 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 blotting.

Results

GSK-3β inhibition was associated with decreased collagen expression and oxidative stress in the ischemic and non-ischemic myocardial tissue compared to control. There was a decrease in pro-fibrotic proteins TGF-β, p-SMAD2/3 and MMP-9 and in pro-apoptotic and oxidative stress proteins; apoptosis inducing factor, the cleaved caspase 3/caspase 3 protein ratio and p-MCL-1 in the GSK-3β inhibited group compared to the control.

Conclusion

In 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 may be having this beneficial effect by downregulating TGF-β/SMAD2/3 signaling and decreasing mitochondrial induced cellular stress.

Publisher URL: www.sciencedirect.com/science

DOI: S002252231830268X