Zhang Xinli, Qu Linbing, Chen Ling, Chen Chen
School of Biomedical Sciences, University of Queensland, St Lucia, Brisbane, Queensland, Australia.
State Key Laboratories of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Physiol Rep. 2018 Feb;6(4). doi: 10.14814/phy2.13612.
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 O -saturated perfusion for single-cell shortening, [Ca ] 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 [Ca ] transients in diabetic cardiomyocytes. Hexarelin reversed the changes in both contraction and [Ca ] . Action potential duration and transient outward potassium current (I ) 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 K currents, intracellular Ca homeostasis and antiapoptotic signaling pathways.
糖尿病性心肌病的特征是舒张期和收缩期心脏功能障碍，但尚无特异性治疗药物。已证明六肽生长激素释放肽（Hexarelin）可通过其受体生长激素促分泌素受体（GHS-R）改善各种类型心肌病的心脏功能。本实验旨在测试Hexarelin对实验性糖尿病状态下心肌细胞的影响。采用链脲佐菌素（STZ，65mg/kg）诱导的糖尿病大鼠模型，以注射溶剂组作为对照。在STZ诱导糖尿病4周后，每日给予Hexarelin（100μg/kg）治疗，持续2周。在饱和氧灌注下通过酶处理分离心肌细胞，用于记录单细胞缩短、[Ca]瞬变和电生理。通过蛋白质免疫印迹法评估GHS-R表达以及凋亡相关信号蛋白Bax、Bcl-2、半胱天冬酶-3和9。实验数据表明，糖尿病心肌细胞的细胞收缩和舒张减弱，同时[Ca]瞬变的上升和下降也受到抑制。Hexarelin可逆转收缩和[Ca]的变化。糖尿病心肌细胞的动作电位时程和瞬时外向钾电流（I）密度显著增加，Hexarelin治疗可逆转这些变化。Hexarelin治疗后，对照组和糖尿病组均观察到生长激素促分泌素受体（GHS-R）表达上调，这也导致Bax、Bcl-2、半胱天冬酶-3和9表达的抗凋亡变化。在STZ诱导的糖尿病大鼠中，Hexarelin能够通过恢复IK电流、细胞内钙稳态和抗凋亡信号通路来改善心肌细胞功能。
