CYP2E1介导酒精性心肌病的心脏纤维化作用及其机制  

Role and its mechanism of CYP2E1 in cardiac fibrosis in alcoholic cardiomyopathy

作　　者：张荣怀[1] 张珍侠 王凯燕 赵良玉 王艺金 王军奎[1] 刘富强[1] 于凯 郭海涛 ZHANG Ronghuai;ZHANG Zhenxia;WANG Kaiyan;ZHAO Liangyu;WANG Yijin;WANG Junkui;LIU Fuqiang;YU Kai;GUO Haitao(First Department of Cardiology,Shaanxi Provincial People’s Hospital,Xi’an 710068,China;Department of Cardiology,Pucheng Hospital of Shaanxi Provincial People’s Hospital;Department of Physiology and Pathophysiology,Air Force Medical University;College of Life Sciences,Northwestern University)

机构地区：[1]陕西省人民医院心血管内一科,西安710068 [2]陕西省人民医院蒲城医院心血管内科 [3]空军军医大学基础医学院生理与病理生理学教研室 [4]西北大学生命科学学院

出　　处：《山西医科大学学报》2023年第9期1217-1222,共6页Journal of Shanxi Medical University

基　　金：陕西省重点研发计划项目(2023-YBSF-466)。

摘　　要：目的探讨细胞色素P450家族成员2E1(CYP2E1)介导酒精性心肌病心肌纤维化的作用及可能的机制。方法将心脏成纤维细胞分为:对照组(control)、酒精组(ethanol,100 mmol/L)、二烯丙基硫醚组(diallyl sulfide,DAS,CYP2E1抑制剂,100μmol/L)及酒精+DAS组(ethanol+DAS);利用激光共聚焦显微镜技术检测心脏成纤维细胞活化为肌成纤维细胞的标志蛋白α-SMA,应用Western blotting检测成纤维细胞中CYP2E1的蛋白表达水平,以及由成纤维细胞生成的细胞间质Ⅰ型胶原(CollagenⅠ)水平和具有调控纤维化的重要细胞因子TGF-β1的水平。将心脏成纤维细胞分为4组:对照组(control)、肿瘤坏死因子β1组(TGF-β1,10 ng/ml)、DAS组(100μmol/L)及TGF-β1+DAS组。利用激光共聚焦显微镜技术检测心脏成纤维细胞活化为肌成纤维细胞的标志蛋白α-SMA。结果与对照组相比,酒精组心脏成纤维细胞CYP2E1、α-SMA及CollagenⅠ蛋白表达水平都显著升高(P<0.01);与酒精组相比,酒精+DAS组酒精对心脏成纤维细胞的上述效应被显著抑制(P<0.05)。同时,与对照组相比,酒精组心脏成纤维细胞TGF-β1蛋白水平显著升高(P<0.01);与酒精组相比,酒精+DAS组心脏成纤维细胞TGF-β1蛋白的水平未受显著影响(P>0.05)。与对照组相比,TGF-β1组α-SMA表达水平显著升高(P<0.01);与TGF-β1组相比,TGF-β1+DAS组α-SMA的表达水平显著降低(P<0.01)。结论酒精通过促进TGF-β1蛋白水平增加,导致CYP2E1蛋白水平升高,刺激心脏成纤维细胞活化成为肌成纤维细胞,并促进细胞外基质生成,最终导致心脏纤维化。Objective To investigate the role and its mechanisms of CYP2E1(cytochrome P4502E1)in mediation of myocardial fibrosis in alcoholic cardiomyopathy.Methods Cardiac fibroblasts were divided into control group,ethanol group(100 mmol/L),diallyl sulfide(DAS,a CYP2E1 inhibitor,100μmol/L)group and ethanol+DAS group.Laser confocal scanning microscopy was used to observe and detectα-SMA,a marker of cardiac fibroblast transferring into cardiac myoblasts.The expression levels of CYP2E1,CollagenⅠand TGF-β1 in cardiac fibroblasts were detected by Western blotting.Cardiac fibroblasts were divided into control group,tumor necrosis factor-β1 group(TGF-β1,10 ng/ml),DAS group(100μmol/L)and TGF-β1+DAS group.Laser confocal scanning microscopy was used to detect the expression ofα-SMA.Results Compared with control group,the expression levels of CYP2E1,α-SMA and CollagenⅠwere significantly increased in ethanol group.However,the above effects of ethanol on cardiac fibroblasts were significantly inhibited in ethanol+DAS group compared with ethanol group(P<0.05).At the same time,compared with control group,the expression of TGF-β1 in ethanol group was significantly increased(P<0.01).The level of TGF-β1 showed no significant difference between ethanol+DAS group and ethanol group(P>0.05).In addition,compared with control group,α-SMA was significantly increased in TGF-β1 group(P<0.01).The expression ofα-SMA was inhibited in TGF-β1+DAS group compared with TGF-β1 group(P<0.01).Conclusion Alcohol can stimulate the transformation of cardiac fibroblasts into myofibroblasts by increasing CYP2E1 expression through the increase of TGF-β1 expression,and promote the production of extracellular matrix,which eventually leads to cardiac fibrosis.

关 键 词：酒精性心肌病 心脏成纤维细胞 心脏纤维化 CYP2E1 TGF-Β1 

分 类 号：R542.2[医药卫生—心血管疾病]