促红细胞生成素通过抑制内质网应激诱导的糖尿病心肌病来减轻大鼠的心脏功能障碍。
Erythropoietin Attenuates Cardiac Dysfunction in Rats by Inhibiting Endoplasmic Reticulum Stress-Induced Diabetic Cardiomyopathy.
机构信息
Department and Institute of Cardiology, Zhongda Hospital, Medical School of Southeast University, No. 87 Dingjiaqiao Street, Nanjing, 210009, Jiangsu, People's Republic of China.
出版信息
Cardiovasc Drugs Ther. 2017 Aug;31(4):367-379. doi: 10.1007/s10557-017-6742-1.
PURPOSE
Enhanced endoplasmic reticulum (ER) stress and down-regulated SERCA2a expression play crucial roles in diabetes. We aimed to verify whether erythropoietin (EPO) attenuates cardiac dysfunction by suppressing ER stress in diabetic rats.
METHODS
Forty male SD rats were randomly divided into four groups: control, EPO-treated control, vehicle-treated diabetic, and EPO-treated diabetic groups. The animals in the EPO-treated control and diabetic groups were administered recombinant human EPO (1000 U/kg body weight) once per week for 12 weeks. RT-PCR and Western blotting assays were performed to detect the expression of 78-kDa glucose-regulated protein precursor (GRP78) and sarcoplasmic/endoplasmic reticulum Ca-ATPase (SERCA2a). We cultured neonatal rat cardiomyocytes and investigated the protective effects of EPO against high glucose (HG)-induced apoptosis. Intracellular calcium levels were measured through confocal microscopy.
RESULTS
We observed increased myocardial GRP78 expression and decreased myocardial SERCA2a expression in diabetic rats. EPO prevented the changes in GRP78, SERCA2a expression and cardiac dysfunction in diabetic rats. The levels of GRP78 protein were significantly reduced in EPO-treated diabetic rats compared with vehicle-treated diabetic rats (GRP78 protein 0.09 ± 0.03 vs. 0.54 ± 0.04, P < 0.01). The levels of the SERCA2a proteins were significantly increased in EPO-treated diabetic rats compared with vehicle-treated diabetic rats (SERCA2a protein 0.60 ± 0.05 vs. 0.13 ± 0.04, P < 0.01). A reduction in apoptosis was observed in the cardiomyocytes treated with 20 U/mL EPO compared with the cardiomyocytes cultured under HG conditions (apoptosis rate 18.9 ± 1.94 vs. 37.9 ± 1.59%, P < 0.01).
CONCLUSIONS
This study demonstrates that EPO treatment improved the parameters of cardiac function following HG-induced injury by suppressing ER stress and inducing SERCA2a expression.
目的
增强内质网（ER）应激和下调 SERCA2a 表达在糖尿病中起关键作用。我们旨在验证促红细胞生成素（EPO）是否通过抑制糖尿病大鼠的 ER 应激来减轻心脏功能障碍。
方法
将 40 只雄性 SD 大鼠随机分为 4 组：对照组、EPO 治疗对照组、 vehicle（赋形剂）治疗糖尿病组和 EPO 治疗糖尿病组。EPO 治疗对照组和糖尿病组的动物每周接受一次重组人 EPO（1000 U/kg 体重）治疗，共 12 周。通过 RT-PCR 和 Western blot 检测 78kDa 葡萄糖调节蛋白前体（GRP78）和肌浆/内质网 Ca-ATP 酶（SERCA2a）的表达。我们培养新生大鼠心肌细胞，并研究 EPO 对高糖（HG）诱导的细胞凋亡的保护作用。通过共聚焦显微镜测量细胞内钙水平。
结果
我们观察到糖尿病大鼠心肌 GRP78 表达增加，SERCA2a 表达减少。EPO 预防了糖尿病大鼠中 GRP78、SERCA2a 表达和心脏功能障碍的变化。与 vehicle 治疗的糖尿病大鼠相比，EPO 治疗的糖尿病大鼠的 GRP78 蛋白水平显著降低（GRP78 蛋白 0.09±0.03 对 0.54±0.04，P<0.01）。与 vehicle 治疗的糖尿病大鼠相比，EPO 治疗的糖尿病大鼠的 SERCA2a 蛋白水平显著增加（SERCA2a 蛋白 0.60±0.05 对 0.13±0.04，P<0.01）。与在高糖条件下培养的心肌细胞相比，用 20 U/mL EPO 处理的心肌细胞中观察到细胞凋亡减少（凋亡率 18.9±1.94 对 37.9±1.59%，P<0.01）。
结论
本研究表明，EPO 治疗通过抑制 ER 应激和诱导 SERCA2a 表达，改善了 HG 诱导损伤后的心脏功能参数。
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