The consequences of long-term glycogen synthase kinase-3 inhibition on normal and insulin resistant rat hearts.

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. Ca(2+)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.

• Authors: T B Flepisi, Amanda Lochner, Barbara Huisamen
• Journal: Cardiovascular drugs and therapy (Cardiovasc Drugs Ther) Vol. 27 Issue 5 Pg. 381-92 (Oct 2013) ISSN: 1573-7241 [Electronic] United States
• PMID: 23820981 (Publication Type: Journal Article)

Chemical References

• Calcium-Binding Proteins
• Insulin Receptor Substrate Proteins
• Irs1 protein, rat
• Irs2 protein, rat
• Protein Kinase Inhibitors
• phospholamban
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• Sarcoplasmic Reticulum Calcium-Transporting ATPases

Topics

• Animals
• Calcium-Binding Proteins (metabolism)
• Diet
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin Resistance
• Male
• Myocardium (metabolism)
• Myocytes, Cardiac (metabolism)
• Obesity (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Wistar
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (metabolism)