Related Experiment Video
Updated: Mar 21, 2026
Modeling and Evaluation of Murine Diabetic Cardiomyopathy Model
Published on: November 29, 2024
The Impact of Chronic Glycogen Synthase Kinase-3 Inhibition on Remodeling of Normal and Pre-Diabetic Rat Hearts
B Huisamen1,2, T Lubelwana Hafver3, D Lumkwana4
1Department of Biomedical Sciences, Division of Medical Physiology, Faculty of Medicine and Health Sciences, University of Stellenbosch, P.O. Box 19063, Tygerberg, 7505, Republic of South Africa. bh3@sun.ac.za.
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 ± 0.50um(2)) 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.
Insights
Glycogen synthase kinase-3 (GSK-3) inhibition in rats led to myocardial hypertrophy, suggesting potential cardiac risks. Further research is needed to determine if these changes are adaptive or maladaptive.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Metabolic Diseases
Background:
- Obesity and type 2 diabetes (T2D) are linked to cardiomyopathy and left ventricular hypertrophy.
- Glycogen synthase kinase-3 (GSK-3) inhibitors are explored for T2D treatment due to improved glucose handling.
- GSK-3 regulates cardiac hypertrophic signaling, posing a risk for myocardial hypertrophy.
Purpose of the Study:
- To investigate the hypothesis that chronic GSK-3 inhibition induces or exacerbates myocardial hypertrophy.
- To assess the impact of GSK-3 inhibition on cardiac structure and function in obese and control rats.
Main Methods:
- Obese and control rats were treated with a GSK-3 inhibitor (CHIR118637) or control diet.
- Biometric, biochemical, and echocardiographic parameters were measured.
- Localization of NFATc3 and GATA4 in cardiomyocytes was determined.
Main Results:
- Obesity induced myocardial hypertrophy, characterized by increased ventricular mass and cardiomyocyte size.
- GSK-3 inhibition increased ventricular mass in control rats and end-diastolic diameter in both groups.
- GSK-3 inhibition led to peri-nuclear localization of NFATc3 and GATA4.
Conclusions:
- GSK-3 inhibition showed indications of myocardial hypertrophy in both control and obese rats.
- The adaptive or maladaptive nature of these cardiac changes requires further investigation.
