DMOG稳定缺氧诱导因子1α改善发绀右心室重构

Stabilization of Hypoxia Inducible Factor-1αby DMOG Inhibits Development of Chronic Hypoxia-Induced Right Ventricular Remodeling

目的探索二甲基乙二酰基甘氨酸(dimethyloxalylglycine,DMOG)是否通过增强缺氧诱导因子1α(hypoxia-inducible factor,HIF-1α)稳定性改善慢性缺氧导致的右心室重构(right ventricular remodeling,RVR)。方法Sprague Dawley大鼠持续低氧4周形成发绀右心室肥厚模型。实验分为常氧组,低氧组,低氧对照组,低氧DMOG组。分别记录各组大鼠体重变化趋势,计算右心室心肥厚指数,Masson染色评估心肌纤维化程度,Western blot检测HIF-1α及促红细胞生成素受体(erythropoietin receptor,EPOR)蛋白的表达,实时聚合酶链反应检测葡萄糖转运蛋白1(glucose transporter 1,GLUT-1)、B淋巴细胞瘤2(B-cell lymphoma-2,Bcl-2)、血管内皮生长因子(vascular endothelial growth factor,VEGF)的水平,ELISA检测血清白细胞介素6(interleukin6,IL-6)水平。结果低氧组HIF-1α水平在2~4周后出现表达下调,而低氧DMOG组大鼠HIF-1α持续稳定表达(P<0.05),注射DMOG显著改善缺氧诱导的大鼠体重下降、右心室肥厚、心肌纤维化等病理表型(P<0.05)。机制研究表明,DMOG升高GLUT-1、Bcl-2、VEGF、EPO表达(P<0.05),降低I型胶原、IL-6表达(P<0.05),EPOR蛋白在发绀心肌中表达亦升高。结论DMOG通过增加血管生成、改善心肌纤维化、减少炎症及能量代谢等明显改善发绀心肌重塑过程,分子机制与其稳定HIF-1α的作用相关。

Objective To explore dimethylglyoxylglycine(DMOG)whether to improve the right ventricular remodeling induced by chronic hypoxia by enhancing the stability of hypoxia inducible factors-1α(HIF-1α).Methods We tested the hypothesis that DMOG prevents the development RVR following chronic hypoxia exposure.Rats were injected with saline or DMOG and exposed to room air or continued hypoxia for 4 wk.The weight change trend of rats was recorded,the weight of right ventricle(RV)and left ventricle+septum(LV+S)were measured,and the right ventricular hypertrophy index(RV/LV+S)was calculated.Masson staining was performed on the right ventricular tissue sections of hypoxic rats to evaluate the degree of myocardial fibrosis.HIF-1αwas detected by RT-PCR and Western blot To investigate the response of myocardial erythropoietin(EPO)and its receptor to hypoxia exposure.In addition,we also studied the effects of DMOG on HIF-1 target genes such as glucose transporter 1(GLUT-1),B-cell lymphoma-2(Bcl-2)and vascular endothelial growth factor(VEGF).Results Compared with hypoxia group,the rats in DMOG group had higher HIF-1αexpression(P<0.05),the trend of weight loss,right ventricular systolic pressure,right ventricular hypertrophy and the degree of myocardial fibrosis were significantly improved(P<0.05).The expression of GLUT-1,Bcl-2,VEGF and EPO increased significantly in DMOG group(P<0.05),and the expression of collagen I and IL-6 decreased significantly(P<0.05).At the same time,the expression of EPOR protein was detected in cyanotic myocardium.Conclusion This study support a role for HIF-1αstabilizers in the treatment of RVR.This provides a new idea for the treatment of clinical cyanosis after RVR.