熊去氧胆酸对异丙肾上腺素诱导的小鼠心肌纤维化的作用  

Effects and mechanisms of ursodeoxycholic acid on isoprenaline-Induced myocardial fibrosis in mice

作　　者：李秀[1] 韩科强 石亚男[1] 门素珍 李舒[1] 孙孟华 董浩[1] 卢景晶 马丽娟[1] 赵敏[1] 李丹[1] 刘巍[1] Li Xiu Han Keqiang Shi Yanan Men Suzhen Li Shu Sun Menghua Dong Hao Lu Jinxing Ma Lijuan Zhao Min Li Dan Liu Wei(Department of Cardiovascular Diseases, the First Affiliated Hospital of Harbin Medical University,Harbin 150001, China)

机构地区：[1]哈尔滨医科大学附属第一医院心内科,150001 [2]辽阳市中心医院心内科

出　　处：《中华医学杂志》2017年第5期387-391,共5页National Medical Journal of China

基　　金：国家自然科学基金面上项目（81270310）,哈尔滨市科技创新人才研究专项资金（杰出青年人才）（2016RAYBJ005）,黑龙江省教育厅海外学人重点项目（1252HQ013）

摘　　要：目的探讨熊去氧胆酸（UDCA）对异丙肾上腺素（ISO）诱导的小鼠心肌纤维化的作用及潜在机制。方法61只雄性昆明小鼠数字表法随机分为正常组、UDCA低剂量组、UDCA高剂量组、螺内酯组和对照组。ISO皮下注射30d构建心肌纤维化模型。HE、Masson染色检测心肌炎症及纤维化程度；免疫组化检测心肌胶原蛋白（Col）I、Ⅲ的表达；蛋白印迹法检测转化生长因子-β1（TGF-β1）、结缔组织生长因子（CTGF）、基质金属蛋白酶2（MMP2）、基质金属蛋白酶9（MMP9）、基质金属蛋白酶抑制剂1（TIMP1）、基质金属蛋白酶抑制剂4（TIMP4）及NF-κB抑制蛋白（IKB）及其磷酸化形式（p—IκB-α）的表达。结果ISO诱导小鼠发生心肌纤维化，CdI和CdⅢ表达显著增加（P〈0．05）；与对照组相比，UDCA组及螺内酯组纤维化程度均显著减轻（P〈0．05），其中UDCA高剂量组纤维化减轻更明显（P〈0．05）；UDCA组及螺内酯组Col I、ColⅢ及TGF-β1的表达减少[UDCA低剂量组（1．52±0．16）、高剂量组（1．02±0．12）、螺内酯组（1．01±0．21）比对照组（2．73±0．12），P〈0．05]；各组间CTGF、MMP2／9及TIMP1／4的表达差异无统计学意义（P〉0．05）。UDCA剂量依赖性地降低p-IκB—α，增加IκB的表达。结论UDCA激活受体TGR5，通过下调NF-κB介导的TGF-β1表达发挥抗小鼠心肌纤维化作用。Objective To investigate the effects and possible mechanisms of ursodeoxycholic acid （UDCA） on myocardial fibrosis in mice. Method To observe the expression of transforming growth factor （TGF） -β1, CTGF, MMPs and the degree of myocardial fibrosis, 61 male Kunming mice were randomly divided into normal group, low dose UDCA group, high dose of UDCA group, spironolactone group, and the control group. Isoproterenol （ISO） injection was given subcutaneously （30 d ） to make the model of myocardial fibrosis. Corresponding anti-fibrosis drugs （UDCA or spironolactone） were given by garage. HE staining and Masson staining were performed to explore the inflammation and fibrosis in the myocardium. The expression of collagen I and collagen III protein was detected by immunohistochemistry to evaluate the degree of fibrosis among the groups. Western blot was used to detect the expression of transforming growth factor, （TGF） -β1, connective tissue growth factor （ CTGF）, matrix metalloproteinase （MMP） -2, -9, tissue inhibitor of metalloproteinase （ TIMP）-4,-1 and anti-phospho-NFKBIA （p-IKB-α） inhibitor of NF-KB （IκB） protein in myocardium. Results HE and Masson staining results showed that in the normal group,myocardial fibrosis is less, while the control group showed a large amount of fibrotic tissue （P 〈 0. 05）. Tissue fibrosis in the low/high dose UDCA group and spironolactoue group was significantly reduced compared with the control group （P 〈 0. 05 ）, in which high dose of UDCA reduces fibrosis more significantly. Immunohistochemistry results showed that collagen I and collagen III protein expression was significantly increased （P 〈 0. 05 ）. Whereas in the low/high UDCA dose group and spironolactone group, collagen I and collagen ]II expression were significantly decreased （P 〈 0.05） , the high UDCA dose group decreased more significantly. Western blot results suggest that TGF^-I expression in the myocardial tissue was significantly increased compared to

关 键 词：熊去氧胆酸 异丙肾上腺素 心肌疾病 胶原 

分 类 号：R542.23[医药卫生—心血管疾病]