复方丹参片调控AT_1介导花生四烯酸PLA2-COX2/5-LOX代谢途径防治心力衰竭的机制研究  

Mechanisms of Fufang Danshen tablets on treating heart failure via regulating AT1-mediated PLA2-COX2/5-LOX metabolic pathway

作　　者：张怡[1] 王勇 孟慧 卢文吉 王启新 张倩 李春 屠鹏飞[1] ZHANG Yi;WANG Yong;MENG Hui;LU Wen-ji;WANG Qi-xin;ZHANG Qian;LI Chun;TU Peng-fei(Modern Research Center for Traditional Chinese Medicine,School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 100029,China;School of Life Sciences,Beijing University of Chinese Medicine,Beijing 100029,China;College of Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China)

机构地区：[1]北京中医药大学中药学院中药现代研究中心,北京100029 [2]北京中医药大学生命科学学院,北京100029 [3]北京中医药大学中医学院,北京100029

出　　处：《中国中药杂志》2018年第12期2593-2599,共7页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金项目(81470191,81673802);北京中医药大学优秀青年科学基金项目(2016-JYB-XJ003,2015-JYB-QNJSZX001,2015-JYB-XYQ001);霍英东教育基金项目(151044);北京市科技新星项目(Z171100001117028);中国科学技术协会人才青年科学家项目(CACM-2017-QNRC2-C13)

摘　　要：心肌纤维化（myocardial fibrosis,MF）是心肌梗死（myocardial infarction,MI）向心力衰竭（heart failure,HF）转化的重要病理生理机制,而心肌细胞内花生四烯酸（arachidonic acid,AA）代谢紊乱在MF的发生发展过程中发挥着重要作用。有文献报道复方丹参片具有抗纤维化的作用,但其具体作用机制尚不明确。该实验通过左冠状动脉前降支结扎术制备MI后HF动物模型,利用超声、血流动力学、病理切片染色、TUNEL和Western blot等技术进行检测,探究复方丹参片抑制MF进而防治HF的药效及其作用机制。结果显示,复方丹参片可以显著提高MI大鼠的左室短轴缩短率（fractional shortening,FS）、射血分数（ejection fraction,EF）、左心室收缩压（left ventricular systolic pressure,LVSP）等心功能指标;此外,可以显著降低血清肌酸激酶同工酶（creatine kinase-MB,CK-MB）、乳酸脱氢酶（lactate dehydrogenase,LDH）的含量;病理结果显示,复方丹参片可以有效减少缺血区心肌组织的炎性细胞浸润,抑制纤维化程度与心肌细胞凋亡;Western blot结果显示复方丹参片可以下调缺血心肌组织中AT1,MMP2,MMP9的含量,并且上调AT2的含量;此外,复方丹参片还可以抑制缺血心肌组织中AA代谢通路中PLA2,P450,COX2,5-LOX的表达。因此,复方丹参片能有效抑制大鼠心肌梗死后缺血区域的纤维化程度,进而延缓其HF进程;其机制与复方丹参片调节AT1介导的AA相关的PLA2-COX2代谢途径相关。Myocardial fibrosis（ MF） is an important pathological change involved in the progress from myocardial infarction（ MI）to heart failure（ HF）. Metabolic disorder of arachidonic acid（ AA） in cardiomyocytes plays an important role in process of MF. Fufang Danshen tablets is a traditional Chinese medicine（ TCM）,which showed significant effect on coronary heart diseases and anti-MF.However,the underlying mechanism of anti-MF remains unclear. In this study,HF animal model of myocardial infarction was established by ligation of left anterior descending coronary artery. The heart function of rats in each group was evaluated by echocardiography and hemodynamic measurement. Histological examination,TUNEL and Western blot were used to detect the levels of MF and proteins related to AA metabolism. As a result,MI significantly decreased the levels of ejection fraction（ EF）,ejection fraction（ FS） and left ventricular systolic pressure（ LVSP）,and these decreases were significantly improved by the treatment of Fufang Danshen tablets. Besides,Fufang Danshen tablets treatment down-regulated the levels of creatine kinase-MB（ CK-MB） and lactate dehydrogenase（ LDH）in serum. HE,Masson and TUNEL staining results showed that Fufang Danshen tablets treatment could inhibit the inflammatory cells infiltration and attenuate the fibrosis and apoptosis to exert cardioprotective effect. Western blot indicated that Fufang Danshen tablets treatment down-regulated the expressions of AT1,MMP2,MM9,while up-regulated the expression of AT2 to inhibit MF. Further mechanism study indicated that Fufang Danshen tablets inhibited MF by down-regulated the expressions of AA metabolism,such as PLA2,P450,COX2 and 5-LOX. In summary,Fufang Danshen tablets can effectively inhibit MF in the ischemic area after MI in rats.The mechanism is related to the regulation of AT1-mediated PLA2-COX2 metabolic pathway.

关 键 词：复方丹参片 心衰 心肌纤维化 花生四烯酸代谢 

分 类 号：R285.5[医药卫生—中药学]