Matsubara H
Department of Medicine II, Division of Endocrine Hypertension and Metabolism and Nephrology, Kansai Medical University, Moriguchi, Osaka, Japan.
Circ Res. 1998;83(12):1182-91. doi: 10.1161/01.res.83.12.1182.
Since the discovery of nonpeptidic ligands, the receptors for angiotensin (Ang) II have been classified into 2 subtypes (Ang II type 1 receptor [AT1-R] and Ang II type 2 receptor [AT2-R]). AT1-R mediates most of the cardiovascular actions of Ang II. AT2-R is expressed at very high levels in the developing fetus. Its expression is very low in the cardiovascular system of the adult. The expression of AT2-R can be modulated by pathological states associated with tissue remodeling or inflammation. In failing hearts or neointima formation after vascular injury, AT2-R is reexpressed in cells proliferating in interstitial regions or neointima and exerts an inhibitory effect on Ang II-induced mitogen signals or synthesis of extracellular matrix proteins, resulting in attenuation of the tissue remodeling. An extreme form of cell growth inhibition ends in programmed cell death, and this process, which is initiated by the withdrawal of growth factors, is also enhanced by AT2-R. Cardiac myocyte- or vascular smooth muscle-specific mice that overexpress AT2-R display an inhibition of Ang II-induced chronotropic or pressor actions, suggesting the role of AT2-R on the activity of cardiac pacemaker cells and the maintenance of vascular resistance. AT2-R also activates the kinin/nitric oxide/cGMP system in the cardiovascular and renal systems, resulting in AT2-R-mediated cardioprotection, vasodilation, and pressure natriuresis. These effects, transmitted by AT2-R, are mainly exerted by stimulation of protein tyrosine or serine/threonine phosphatases in a Gi protein-dependent manner. The expression level of AT2-R is much higher in human hearts than in rodent hearts, and the AT2-R-mediated actions are likely enhanced, especially by clinical application of AT1-R antagonists. Thus, in this review, the regulation of AT2-R expression, its cellular localization, its pathological role in cardiovascular and kidney diseases, and pharmacotherapeutic effects of AT2-R stimulation are discussed.
自从发现非肽类配体以来，血管紧张素（Ang）II受体已被分为2种亚型（血管紧张素II 1型受体[AT1-R]和血管紧张素II 2型受体[AT2-R]）。AT1-R介导了Ang II的大部分心血管作用。AT2-R在发育中的胎儿中高水平表达。在成年人的心血管系统中其表达非常低。AT2-R的表达可被与组织重塑或炎症相关的病理状态所调节。在衰竭心脏或血管损伤后的新生内膜形成过程中，AT2-R在间质区域或新生内膜中增殖的细胞中重新表达，并对Ang II诱导的促有丝分裂信号或细胞外基质蛋白的合成发挥抑制作用，从而导致组织重塑的减轻。细胞生长抑制的极端形式以程序性细胞死亡告终，这个由生长因子撤除引发的过程也会被AT2-R增强。过表达AT2-R的心肌细胞或血管平滑肌特异性小鼠表现出对Ang II诱导的变时或升压作用的抑制，提示AT2-R对心脏起搏细胞活性和血管阻力维持的作用。AT2-R还激活心血管和肾脏系统中的激肽/一氧化氮/cGMP系统，从而导致AT2-R介导的心脏保护、血管舒张和压力性利钠作用。这些由AT2-R传递的效应主要通过以Gi蛋白依赖性方式刺激蛋白酪氨酸或丝氨酸/苏氨酸磷酸酶来发挥作用。AT2-R在人类心脏中的表达水平远高于啮齿动物心脏，并且AT2-R介导的作用可能会增强，尤其是通过AT1-R拮抗剂的临床应用。因此，在本综述中，将讨论AT2-R表达的调节、其细胞定位、其在心血管和肾脏疾病中的病理作用以及AT2-R刺激的药物治疗效果。
