Angiotensin II Type 2 (AT2) Receptor Singnal and Cardiovascular Action

血管紧张素 II 2 型 (AT2) 受体信号和心血管作用

• 批准号: 11470166
• 负责人: MATSUBARA Hiroaki
• 金额: $ 9.47万
• 依托单位: Kansai Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470166/
• 关键词: angiotensin II receptor; angiotensin II AT1 receptor; angiotensin II AT2 receptor; angiotensin II type 1 receptor; angiotensin II type 2 receptor; ブラジキニン; AT1受容体; AT2受容体

Due to the discovery of nonpeptidic ligands the receptors for angiotensin (Angl II are classified into two subtypes (AT1-R and AT2-R). AT1-R. mediates most of the cardiovascular actions of Ang II. AT2-R is expressed at very high levels in the developing fetlrs. Its expression is vefy low in the cardiovascular system of the adult. The expression of AT2-R can be modulated by pathological states associated with tissue remodeling or inflaimmation. In failing hearts or neointima fonnation after vascular injury, AT2-R is re-expressed 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, restnlting in AT2-R-mediated cardioprotection, vasodilation and pressure natriuresis. These effects, transmitted by AT2-R, are mairily 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 rodept hearts, and the AT2-R-mediated actions are likely enhanced, especially by clinical application of AT1-R antagonists. Thus, in this review, the regtilation of AT2-R expression, its cellular localization, its pathological role in cardiovascular and kidney ciseases, and phamlacotherapeutic effects of AT2-R stimulation are discussed.

由于非肽配体的发现，血管紧张素（Angl II）的受体分为两种亚型（AT 1-R和AT 2-R）。AT1-R。介导血管紧张素II的大部分心血管作用。AT 2-R在发育中的胚胎中以非常高的水平表达。它在成年人心血管系统中的表达非常低。AT 2-R的表达可以受到与组织重塑或炎症相关的病理状态的调节。在衰竭的心脏或血管损伤后的新生内膜形成中，AT 2-R在间质区或新生内膜中增殖的细胞中重新表达，并对Ang II诱导的有丝分裂原信号或细胞外基质蛋白的合成产生抑制作用，导致组织重塑减弱。细胞生长抑制的一种极端形式以程序性细胞死亡结束，而这一过程由生长因子的撤回引发，也被AT 2-R增强。过表达AT 2-R的心肌细胞或血管平滑肌特异性小鼠显示对Ang II诱导的变时性或升压作用的抑制，表明AT 2-R对心脏起搏细胞活性和维持血管阻力的作用。AT 2-R还激活激肽/硝酸盐。氧化物/cGMP系统在心血管和肾脏系统中的作用，在AT 2-R介导的心脏保护、血管舒张和压力性尿钠排泄中起作用。这些作用由AT 2-R传递，主要通过刺激蛋白酪氨酸或丝氨酸/苏氨酸磷酸酶以Gi蛋白依赖性方式发挥。AT 2-R在人心脏中的表达水平远高于正常心脏，AT 2-R介导的作用可能会增强，尤其是AT 1-R拮抗剂的临床应用。本文就AT_2-R的表达调控、细胞定位、在心血管和肾脏疾病中的病理作用以及AT_2-R的药理作用作一综述。

项目成果

Uchiyama-Tanaka Y, Matsubara H, Nozawa Y, Murasawa S, Mori Y, Kosaki A, Maruyama K, Masaki H, Shibasaki Y, Fujiyama S, Nose A, Iba O, Hasagawa T, Tateishi E, Higashiyama S, Iwasaka T.: "Angiotensin II signaling and HB-EGF shedding via metalloproteinase in

内山田中 Y、松原 H、野泽 Y、村泽 S、森 Y、小崎 A、丸山 K、正崎 H、柴崎 Y、富士山 S、鼻子 A、伊巴 O、长谷川 T、立石 E、东山 S、岩坂 T。

Moriguchi Y,Matsubara H 他10名: "Angiotensin II-Induced Transactivation of EGF Receptor Regulates Fibronectin and TGF-β Synthesis via Transcriptional and Post-transcriptional Mechanisms."Circ Res. 84(9). 1073-1084 (1999)

Moriguchi Y、Matsubara H 和其他 10 人：“血管紧张素 II 诱导的 EGF 受体反式激活通过转录和转录后机制调节纤连蛋白和 TGF-β 合成”，Circ Res 84(9)。

Matsubara H, 他: "Effect of angiotensinII type 2 receptor on tyrosine kinase Pyk 2 and c-Jun NH2-terminal kinase・・・"Biochem Biophys Res Commun. 282. 1085-1091 (2001)

Matsubara H 等人：“血管紧张素 II 2 型受体对酪氨酸激酶 Pyk 2 和 c-Jun NH2-末端激酶的影响...”Biochem Biophys Res Commun. 282. 1085-1091 (2001)

Fujiyama S,Matsubara H 他11名: "Angiotensin II initiates tyrosine kinase Pyk2-dependent signalings leading to activation of Racl-mediated c-Jun NH2-terminal kinase."J Biol Chem. 275(35). 26856-26863 (2000)

Fujiyama S、Matsubara H 和其他 11 人：“血管紧张素 II 启动酪氨酸激酶 Pyk2 依赖性信号传导，导致 Racl 介导的 c-Jun NH2 末端激酶的激活。”J Biol Chem 275(35)。

Tsutsumi Y,Matsubara H 他12名: "Angiotensin II Type 2 Receptor Is Up-Regulated in Human Heart with Interstitial Fibrosis and Cardiac Fibroblasts Are the Major Cell Type for Its Expression."Circ Res. 83(10). 1035-1046 (1998)

Tsutsumi Y、Matsubara H 和其他 12 人：“血管紧张素 II 2 型受体在间质纤维化的人类心脏中上调，心脏成纤维细胞是其表达的主要细胞类型。”Circ Res 83(10)。 1998）