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The Consequences of Long-Term Glycogen Synthase Kinase-3 Inhibition on Normal and Insulin Resistant Rat Hearts

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Abstract

Background

Glycogen synthase kinase-3 (GSK-3) is a serine-threonine protein kinase, discovered as a regulator of glycogen synthase. GSK-3 may regulate the expression of SERCA-2a potentially affecting myocardial contractility. It is known to phosphorylate and inhibit IRS-1, thus disrupting insulin signalling. This study aimed to determine whether myocardial GSK-3 protein and its substrate proteins are dysregulated in obesity and insulin resistance, and whether chronic GSK-3 inhibition can prevent or reverse this.

Methods

Weight matched male Wistar rats were rendered obese by hyperphagia using a special diet (DIO) for 16 weeks and compared to chow fed controls. Half of each group was treated with the GSK-3 inhibitor CHIR118637 (30 mg/kg/day) from week 12 to16 of the diet period. Biometric and biochemical parameters were measured and protein expression determined by Western blotting and specific antibodies. Ca2+ATPase activity was determined spectrophotometrically. Cardiomyocytes were prepared by collagenase perfusion and insulin stimulated 2-deoxy-glucose uptake determined.

Results

DIO rats were significantly heavier than controls, associated with increased intra-peritoneal fat and insulin resistance. GSK-3 inhibition did not affect weight but improved insulin resistance, also on cellular level. It had no effect on GSK-3 expression but elevated its phospho/total ratio and elevated IRS-2 expression. Obesity lowered SERCA-2a expression and activity while GSK-3 inhibition alleviated this. The phospho/total ratio of phospholamban underscored inhibition of SERCA-2a in obesity. In addition, signs of myocardial hypertrophy were observed in treated control rats.

Conclusion

GSK-3 inhibition could not reverse all the detrimental effects of obesity but may be harmful in normal rat hearts. It regulates IRS-2, SERCA-2a and phospholamban expression but not IRS-1.

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Authors and Affiliations

  1. Department of Medicine, Division of Pharmacology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, 7505, South Africa

    T. B. Flepisi

  2. Diabetes Discovery Platform, Medical Research Council, Tygerberg, 7505, South Africa

    Barbara Huisamen

  3. Department of Biomedical Sciences, Division of Medical Physiology, Faculty of Health Sciences, University of Stellenbosch, P.O. Box 19063, Tygerberg, 7505, Republic of South Africa

    Amanda Lochner & Barbara Huisamen

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  1. T. B. Flepisi
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Correspondence to Barbara Huisamen.

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Flepisi, T.B., Lochner, A. & Huisamen, B. The Consequences of Long-Term Glycogen Synthase Kinase-3 Inhibition on Normal and Insulin Resistant Rat Hearts. Cardiovasc Drugs Ther 27, 381–392 (2013). https://doi.org/10.1007/s10557-013-6467-8

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