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 (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.

The CD36-PPARγ Pathway in Metabolic Disorders

“…Consistent with such a GH-independent role, peripheral ghrelin actions have been linked to clinical implications of cardiovascular disease, insulin resistance, and obesity [ 31 , 56 , 57 , 58 , 59 ]. Likewise, GH-independent effects on fat metabolism, cardioprotection, hemodynamic control, and bone cell differentiation have been reported for GHRPs [ 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. Hence, such peripheral effects of GHRPs are thought to play important roles in energy homeostasis, adiposity and vascular integrity and identify the GHRPs as highly promising therapeutic targets in metabolic diseases.…”

Development and Characterization of an 18F-labeled Ghrelin Peptidomimetic for Imaging the Cardiac Growth Hormone Secretagogue Receptor

“…There are also changes in myocardial GHSR1a levels and messenger RNA in congestive heart failure in humans. 8 We 8 and others 34 have shown that myocardial GHSR1a decreases during the progression of diabetic cardiomyopathy, with a negative correlation between GHSR1a and development of impaired glucose tolerance. 8 Therefore, GHSR1a may be a biomarker for cardiomyopathies or heart failure, and developing radioligand-based imaging agents that target GHSR1a may complement existing imaging modalities in the detection of changes in heart function that may indicate onset of heart disease or heart failure.…”