TAK1/NF-κB在小鼠心肌肥厚中的变化及意义  

Changes and Significance of TAK1/NF-κB Pathway in Cardiac Hypertrophy in Mice

作　　者：周恒[1] 唐其柱[1] 沈涤非[1] 严玲[1] 卞洲艳[1] 袁园 Zhou Heng;Tang Qizhu;Shen Difei(Department of Cardiology,Renmin Hospital of Wuhan University,Hubei Key Laboratory of Metabolic and Chronic Diseases,Hubei 430060,China)

机构地区：[1]武汉大学人民医院心血管内科、代谢与相关慢病湖北省重点实验室,430060

出　　处：《医学研究杂志》2020年第5期31-35,共5页Journal of Medical Research

基　　金：国家自然科学基金资助项目(重点项目)(81530012);国家自然科学基金资助项目(面上项目)(81770399);国家重点研发计划项目(2018YFC1311300);国家卫生和计划生育委员会医药卫生科技发展研究中心基金资助项目(2016ZX-008-01);中央高校基本科研业务费专项资金资助项目(2042018kf0121)。

摘　　要：目的研究转化生长因子活化激酶1/核因子-κB(TAK1/NF-κB)与炎性反应在心肌肥厚中的作用,探索心肌肥厚的分子机制并寻找潜在的防治靶点。方法使用野生型C57BL/6J小鼠,以主动脉缩窄术(AB)建立压力负荷诱导的心肌肥厚模型,假手术(Sham)组作为对照组。AB术后8周超声心动图评估小鼠心室结构与功能,处死小鼠称量心脏质量。HE与PSR进行心肌组织病理学与纤维化。CD68免疫荧光检测单核-吞噬细胞浸润,实时定量RT-PCR检测炎性反应标志物的表达,Western blot法检测TAK1/NF-κB通路蛋白质磷酸化水平。结果与Sham组比较,AB组小鼠的室壁厚度、室腔大小及心脏质量/体质量明显增加(P<0.05),心功能下降(P<0.05),心肌细胞横截面积与胶原沉积量显著增大(P<0.05)。此外,AB组心肌组织中CD68阳性细胞数明显增多(P<0.05),TNF-α与IL-1β等炎性反应标志物的mRNA表达水平明显升高(P<0.05);AB组TAK1、κB抑制蛋白激酶β与κB抑制蛋白α(IκBα)的磷酸化水平较对照组明显上调,IκBα总蛋白水平降低,NF-κB p65磷酸化水平增加。结论压力负荷诱导的心肌肥厚伴有TAK1/NF-κB通路激活与心肌组织炎性浸润,提示TAK1/NF-κB参与了心肌肥厚的发生、发展。Objective To study the role of transforming growth factor-activated kinase 1/nuclear factor-κB(TAK1/NF-κB)and inflammation in cardiac hypertrophy,to explore the molecular mechanism underlying cardiac hypertrophy and to find potential targets for prevention and treatment.Methods A pressure-induced cardiac hypertrophy model was established in wild C57BL/6J mice by aortic binding(AB),and the sham group was used as control.The ventricular structure and function of mice were assessed by echocardiography 8 weeks after AB,and then the mice were killed and the hearts were weighed.HE and PSR were used for myocardial histopathology and fibrosis.CD68 immunofluorescence was performed to detect monocyte/macrophage infiltration,real-time quantitative RT-PCR was used to examine the expression of inflammatory markers,and Western blot was used to evaluate protein phosphorylation in TAK1/NF-κB pathway.Results Compared with Sham group,the thickness of ventricular wall,size of ventricular chamber,cardiac dysfunction and the ratio of heart weight to body weight in AB group increased significantly(P<0.05),as well as the cross-sectional area of cardiomyocytes and the collagen deposition(P<0.05).In addition,the number of CD68 positive cells in myocardium of AB group increased(P<0.05)and the expression levels of TNF-αand IL-1βelevated(P<0.05).The phosphorylation levels of TAK1,IKKβand IκBαin AB group were significantly higher than those in Sham group.The total protein level of IκBαdecreased,and the phosphorylation level of NF-κB increased(P<0.05).Conclusion Cardiac hypertrophy induced by pressure overload is associated with the activation of TAK1/NF-κB pathway and inflammation infiltration in myocardium,suggesting that TAK1/NF-κB pathway is involved in the development of cardiac hypertrophy.

关 键 词：心肌肥厚 转化生长因子活化激酶1 核因子-ΚB 炎性反应 心力衰竭 

分 类 号：R542[医药卫生—心血管疾病]