Abstract 13634: Glycogen Synthase Kinase-3 Inhibition: Good or Bad for the Heart?
Glycogen synthase kinase-3 (GSK-3) is a ser-thr kinase regulating glycogen synthesis and a known role player in cardioprotection. Myocardial GSK-3 may (i) regulate expression of SERCA-2a, affecting contractility (ii) inhibit IRS-1 disrupting insulin signalling (iii) activate hypertrophic signalling. GSK-3 inhibitors are developed for clinical use treating e.g. affective disorders and type 2 diabetes.
Aim: to study the myocardial effects of chronic GSK-3 inhibition, using pre-diabetic rats.
Methods: Diet-induced obese Wistar rats (DIO) were compared to age matched controls (C), half of each group treated for 4 wks with a GSK-3 inhibitor (CHIR118637@30mg/kg/day). Glucose tolerance, biometric & biochemical parameters were determined, protein expression (western blot) and Ca2+ATPase activity ascertained in snap-frozen hearts and cardiomyocytes used to determine insulin sensitivity, cell size and NFATc3 and GATA4 localization
Results: (i) CHIR did not affect body weight or intraperitoneal fat; (ii) DIO lowered SERCA-2a expression by 66% and inhibited phospholamban while CHIR improved both (iii) DIO lowered IRS-1 levels by 65% and CHIR upregulated IRS-2 in C and DIO by >140% , but not IRS-1 (iv) DIO caused insulin resistance while CHIR improved this by positively modulating insulin signalling (Akt, GSK-3) reflected in enhanced cardiomyocyte insulin sensitivity (Basal gluc uptake: DIO 24% lower, CHIR C 43% & DIO 63% higher; 100nM Ins: DIO 46% lower, CHIR C 16% & DIO 113% higher (v) CHIR increased left ventricular weight and cardiomyocyte size in C animals and translocated NFATc3 and GATA4 to the nucleus.
Conclusion: chronic GSK-3 inhibition improved glucose tolerance and insulin sensitivity but showed clear signs of inducing cardiac hypertrophy, especially in normal animals.
- © 2013 by American Heart Association, Inc.