血管紧张素AT_1受体激活与阻断机制研究进展  

Progress in the Mechanisms of Activation and Inhibition of Angiotensin Ⅱ Type 1 Receptor

作　　者：杨茗[1] 蒋国良[1] 邹云增[1] YANG Ming JIANG Guoliang ZOU Yunzeng(Department of Cardiology, Shanghai lnstitute of Cardiovascular Diseases. Zhongshan Hospital Affiliated to Fudan University Shanghai 200032, Chin)

机构地区：[1]复旦大学附属中山医院心内科上海市心血管病研究所,上海200032

出　　处：《药学进展》2017年第7期509-514,共6页Progress in Pharmaceutical Sciences

摘　　要：血管紧张素Ⅱ(AngⅡ)1型受体(AT_1-R)是G蛋白偶联受体家族成员之一,主要表达在细胞膜上,为7次跨膜结构蛋白。其活化与心血管疾病的发生发展密切相关。以往研究认为心肌组织及微循环局部产生的AngⅡ通过自分泌或旁分泌的方式激活AT_1-R从而引起心肌细胞肥大的发生发展。最近研究发现高血压产生的压力超负荷可不依赖AngⅡ直接激活AT_1-R,通过受体下游信号分子介导心肌损伤。而有关AT1-R如何参与容量负荷介导的心肌肥厚机制目前了解甚少。AT_1-R阻滞剂(ARB)通常可与AngⅡ竞争性拮抗,抑制AT_1-R活性发挥降压和靶器官的保护作用。而部分ARB不仅拮抗AngⅡ对AT_1-R的激活还可抑制压力超负荷对AT_1-R的激活,这种具有不依赖激动剂存在的受体抑制效应被定义为反向激动作用。综述AngⅡ依赖性和机械应力直接激活AT_1-R的研究进展,并讨论AT_1-R的拮抗和反向激动效应在心血管保护中的临床意义。As a member of the seven transmembrane G protein-coupled receptor family, angiotensin II （AnglI） type 1 receptor （AT1-R） is expressed on cell membrane and plays a critical role in the development of many cardiovascular diseases. Previous studies have shown that AT1-R is activated by AnglI locally produced and secreted in heart muscle and microcireulation through autocrine/paracrine mechanisms, leading to overload-induced cardiac hypertrophy. However, ours and other recent studies have reported that AT1-R can be directly activated by mechanical stresses resulted from hypertension in an AngII-independent manner and mediate pressure overload-induced cardiac hypertrophy through downstream signaling pathways. However, the mechanism of AT1-R activation by volume overload remains largely unknown. AT1-R blocker （ARB）, one major type of antihypertensive drugs, usually inhibits the activation of AT1-R through competitively antagonizing ligand. However, some ARBs can antagonize activation of AT1-R by AnglI and mechanical stress. This receptor antagonism that is independent of agonist presence is termed as inverse agonism. This review summarizes the research progresses in AngII- and mechanical stress-dependent activation of AT1-R and discusses clinical relevance of antagonism and inverse agonism of AT1-R in cardiovascular protections.

关 键 词：血管紧张素Ⅱ 血管紧张素Ⅱ1型受体 血管紧张素Ⅱ受体阻滞剂 反向激动作用 

分 类 号：R54[医药卫生—心血管疾病] R962[医药卫生—内科学]