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 (I to) 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 I to K+ currents, intracellular Ca2+ homeostasis and antiapoptotic signaling pathways.
Highlights
Diabetic cardiomyopathy (DCM) has been recognized for decades after Rubler first found this clinical entity without the presence of hypertension or coronary artery diseases in 1972 (Rubler et al 1972)
Body and heart weight significantly elevated in both hexarelin-treated control (HC) and hexarelin-treated diabetic (HD) rats compared to nontreated control (NC) and nontreated diabetes (ND) rats respectively
Defects of [Ca2+]i handling was associated with depressed contractility, prolonged AP duration (APD) and mitochondrial signaling-initiated apoptosis in STZ-induced diabetic cardiomyocytes, implicating these alterations contributed to the development of diabetic cardiomyopathy
Summary
Diabetic cardiomyopathy (DCM) has been recognized for decades after Rubler first found this clinical entity without the presence of hypertension or coronary artery diseases in 1972 (Rubler et al 1972). It is characterized by cardiac dysfunction initiated by significantly diastolic disorders. Echocardiography studies showed that systolic dysfunction often occurred long after establishment of diastolic dysfunction (Petrie et al 2002). Defect in dynamic changes of intracellular calcium ([Ca2+]i) occurred causing reduced cardiac contraction force and relaxation velocity (Choi et al 2002; Rithalia et al 2004).
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