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血管紧张素II-1型受体自身抗体通过激活心肌成纤维细胞参与心肌纤维化

郝韦韦¹, 张苏丽¹, 孙艳¹, 白丽娜¹, 边经纬¹, 于海存¹, 尹晓辰¹, 王鹏丽¹, 刘慧荣^1,2,*

¹首都医科大学基础医学院生理学与病理生理学系，北京 100069；²首都医科大学代谢紊乱相关心血管疾病北京市重点实验室，北京 100069

摘要

心肌纤维化(myocardial fibrosis, MF)是造成心衰患者心脏重构的重要病理过程，但其病因并不完全清楚。已知血管紧张素II-1型受体自身抗体(angiotensin II type 1 receptor autoantibody, AT1-AA)存在于心衰患者体内，但该抗体能否直接导致MF尚不明确。本文旨在探讨AT1-AA致MF的作用及其对心肌成纤维细胞(cardiac fibroblasts, CFs)的影响。通过主动免疫法建立AT1-AA阳性大鼠模型，于主动免疫8周时检测各指标，小动物心脏超声结果显示，AT1-AA阳性组大鼠心脏舒缩功能下降，心腔扩大、室壁变薄；HE染色结果显示，AT1-AA阳性组大鼠心肌纤维走向紊乱，有断裂现象；Masson染色结果显示，AT1-AA阳性组大鼠心肌间质和血管周围的胶原纤维沉积明显增多(P < 0.05)；血压测量结果显示，AT1-AA不会引起大鼠的血压和心率变化。AT1-AA作用于分离培养的原代乳鼠CFs 48 h后，用CCK-8法和免疫荧光法检测CFs增殖情况，结果显示，AT1-AA可显著促进CFs增殖(P < 0.001)；Western blot结果显示AT1-AA显著促进CFs中胶原蛋白I (collagen I, Col I)、Col III、基质金属蛋白酶-2 (matrix metalloproteinase-2, MMP-2)和MMP-9的表达(P < 0.05)。以上结果提示，AT1-AA可能通过激活大鼠CFs导致MF，进而导致心功能下降。

关键词： 血管紧张素II-1型受体自身抗体; 心肌纤维化; 心肌成纤维细胞; 心脏重构 ; 心功能不全

分类号：R363

Angiotensin II type 1 receptor autoantibody induces myocardial fibrosis by activating cardiac fibroblasts

HAO Wei-Wei¹, ZHANG Su-Li¹, SUN Yan¹, BAI Li-Na¹, BIAN Jing-Wei¹, YU Hai-Cun¹, YIN Xiao-Chen¹, WANG Peng-Li¹, LIU Hui-Rong^1,2,*

¹Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China；²Beijing Key Laboratory of Cardiovascular Diseases and Related Metabolic Dysfunction, Capital Medical University, Beijing 100069, China

Abstract

Myocardial fibrosis (MF) is an important pathological process of cardiac remodeling in patients with heart failure; however its etiology has not been clear. It has been known that the angiotensin II type 1 receptor autoantibody (AT1-AA) is present in patients with heart failure, but it is unclear whether this antibody directly causes MF. In this study, we investigated the role of AT1-AA in MF and its effects on cardiac fibroblasts (CFs). The AT1-AA positive rat model was established by active immunization method, and the measurement of indexes were made in the 8th week after active immunity. The results of heart echocardiography showed that the cardiac systolic and diastolic functions of AT1-AA positive rats were impaired with reduced left ventricular wall thickness and enlarged heart chambers. HE staining results showed that the myocardial fibers were disorganized and ruptured, and Masson staining revealed that the area of collagen fibers around the myocardium and coronary arteries was significantly increased in AT1-AA positive group compared with that of the control group (P < 0.05). Moreover, primary CFs isolated from neonatal rats were cultured and treated with AT1-AA for 48 h. CCK-8 and immunofluorescence staining results showed that AT1-AA enhanced proliferation rate of CFs (P < 0.001), and Western blot results showed that AT1-AA significantly increased expressions of collagen I (Col I), Col III, matrix metalloproteinase-2 (MMP-2) and MMP-9 in CFs (all P < 0.05). Taken together, these results suggest that AT1-AA may induce MF and cardiac dysfunction via activating CFs.

Key words: angiotensin II type 1 receptor autoantibody; myocardial fibrosis; cardiac fibroblasts; cardiac remodeling ; heart failure

收稿日期：2018-02-01　　录用日期：2018-02-01

通讯作者：刘慧荣　　E-mail: liuhr2000@126.com

DOI: 10.13294/j.aps.2018.0055

引用本文：

郝韦韦, 张苏丽, 孙艳, 白丽娜, 边经纬, 于海存, 尹晓辰, 王鹏丽, 刘慧荣. 血管紧张素II-1型受体自身抗体通过激活心肌成纤维细胞参与心肌纤维化[J]. 生理学报 2018; 70 (4): 343-353.

HAO Wei-Wei, ZHANG Su-Li, SUN Yan, BAI Li-Na, BIAN Jing-Wei, YU Hai-Cun, YIN Xiao-Chen, WANG Peng-Li, LIU Hui-Rong. Angiotensin II type 1 receptor autoantibody induces myocardial fibrosis by activating cardiac fibroblasts. Acta Physiol Sin 2018; 70 (4): 343-353 (in Chinese with English abstract).