Improvement of cardiomyocyte function by in vivo hexarelin treatment in streptozotocin-induced diabetic rats

Abstract

Diabetic cardiomyopathy is characterized by diastolic and systolic cardiac dysfunction, yet no therapeutic drug to specifically treat it. Hexarelin has been demonstrated to improve heart function in various types of cardiomyopathy via its receptor GHS-R. This experiment aims to test the effect of hexarelin on cardiomyocytes under experimental diabetes. Streptozotocin (STZ, 65 mg/kg)-induced diabetic rat model was employed with vehicle injection group as control. Daily hexarelin (100 μg/kg) treatment was performed for 2 weeks after 4-week STZ-induced diabetes. Cardiomyocytes were isolated by enzyme treatment under O2-saturated perfusion for single-cell shortening, [Ca2+]i transient, and electrophysiology recordings. GHS-R expression and apoptosis-related signaling proteins Bax, Bcl-2, caspase-3 and 9, were assessed by western blot. Experimental data demonstrated a reduced cell contraction and relaxation in parallel with depressed rise and fall of [Ca2+]i transients in diabetic cardiomyocytes. Hexarelin reversed the changes in both contraction and [Ca2+]i. Action potential duration and transient outward potassium current (Ito) density were dramatically increased in diabetic cardiomyocytes and hexarelin treatment reverse such changes. Upregulated GHS receptor (GHS-R) expression was observed in both control and diabetic groups after hexarelin treatment, which also caused antiapoptotic changes of Bax, Bcl-2, caspase-3 and 9 expression. In STZ-induced diabetic rats, hexarelin is able to improve cardiomyocyte function through recovery of Ito K+ currents, intracellular Ca2+ homeostasis and antiapoptotic signaling pathways.