Published in:
01-06-2016 | ORIGINAL ARTICLE
The Impact of Chronic Glycogen Synthase Kinase-3 Inhibition on Remodeling of Normal and Pre-Diabetic Rat Hearts
Published in: Cardiovascular Drugs and Therapy | Issue 3/2016
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Purpose
There is an ongoing search for new drugs and drug targets to treat diseases like Alzheimer’s disease, cancer and type 2 diabetes (T2D). Both obesity and T2D are characterized by the development of a cardiomyopathy associated with increased hypertension and compensatory left ventricular hypertrophy.
Small, specific glycogen synthase kinase-3 (GSK-3) inhibitors were developed to replace lithium chloride for use in psychiatric disorders. In addition, they were advocated as treatment for T2D since GSK-3 inhibition improves blood glucose handling. However, GSK-3 is a regulator of hypertrophic signalling in the heart via phosphorylation of NFATc3 and β-catenin respectively. In view of this, we hypothesized that chronic inhibition of GSK-3 will induce myocardial hypertrophy or exacerbate existing hypertrophy.
Methods
Rats with obesity-induced prediabetes were treated orally with GSK-3 inhibitor (CHIR118637 (CT20026)), 30 mg/kg/day for the last 8 weeks of a 20-week diet high in sugar content vs a control diet. Biometric and biochemical parameters were measured, echocardiography performed and localization and co-localization of NFATc3 and GATA4 determined in cardiomyocytes.
Results
Obesity initiated myocardial hypertrophy, evidenced by increased ventricular mass (1.158 ± 0.029 vs 0.983 ± 0.03 g) and enlarged cardiomyocytes (18.86 ± 2.25 vs 14.92 ± 0.50um2) in association with increased end-diastolic diameter (EDD = 8.48 ± 0.11 vs 8.15 ± 0.10 mm). GSK-3 inhibition (i) increased ventricular mass only in controls (1.075 ± 0.022 g) and (ii) EDD in both groups (controls: 8.63 ± 0.07; obese: 8.72 ± 0.15 mm) (iii) localized NFATc3 and GATA4 peri-nuclearly.
Conclusion
Indications of onset of myocardial hypertrophy in both control and obese rats treated with a GSK-3 inhibitor were found. It remains speculation whether these changes were adaptive or maladaptive.