Masaki H, Kurihara T, Yamaki A, Inomata N, Nozawa Y, Mori Y, Murasawa S, Kizima K, Maruyama K, Horiuchi M, Dzau V J, Takahashi H, Iwasaka T, Inada M, Matsubara H
Department of Medicine II, Kansai Medical University, Osaka 570-8507, Japan.
J Clin Invest. 1998 Feb 1;101(3):527-35. doi: 10.1172/JCI1885.
Angiotensin (Ang) II has two major receptor isoforms, AT1 and AT2. Currently, AT1 antagonists are undergoing clinical trials in patients with cardiovascular diseases. Treatment with AT1 antagonists causes elevation of plasma Ang II which selectively binds to AT2 and exerts as yet undefined effects. Cardiac AT2 level is low in adult hearts, whereas its distribution ratio is increased during cardiac remodeling and its action is enhanced by application of AT1 antagonists. Although in AT2 knock-out mice sensitivity to the pressor action of Ang II was increased, underlying mechanisms remain undefined. Here, we report the unexpected finding that cardiac-specific overexpression of the AT2 gene using alpha-myosin heavy chain promoter resulted in decreased sensitivity to AT1-mediated pressor and chronotropic actions. AT2 protein undetectable in the hearts of wild-type mice was overexpressed in atria and ventricles of the AT2 transgenic (TG) mice and the proportions of AT2 relative to AT1 were 41% in atria and 45% in ventricles. No obvious morphological change was observed in the myocardium and there was no significant difference in cardiac development or heart to body weight ratio between wild-type and TG mice. Infusion of Ang II to AT2 TG mice caused a significantly attenuated increase in blood pressure response and the change was completely blocked by pretreatment with AT2 antagonist. This decreased sensitivity to Ang II-induced pressor action was mainly due to the AT2-mediated strong negative chronotropic effect and exerted by circulating Ang II in a physiological range that did not stimulate catecholamine release. Isolated hearts of AT2 transgenic mice perfused using a Langendorff apparatus also showed decreased chronotropic responses to Ang II with no effects on left ventricular dp/dt max values, and Ang II-induced activity of mitogen-activated protein kinase was inhibited in left ventricles in the transgenic mice. Although transient outward K+ current recorded in cardiomyocytes from AT2 TG mice was not influenced by AT2 activation, this study suggested that overexpression of AT2 decreases the sensitivity of pacemaker cells to Ang II. Our results demonstrate that stimulation of cardia AT2 exerts a novel antipressor action by inhibiting AT1-mediated chronotropic effects, and that application of AT1 antagonists to patients with cardiovascular diseases has beneficial pharmacotherapeutic effects of stimulating cardiac AT2.
血管紧张素（Ang）II有两种主要的受体亚型，即AT1和AT2。目前，AT1拮抗剂正在心血管疾病患者中进行临床试验。用AT1拮抗剂治疗会导致血浆Ang II升高，后者选择性地与AT2结合并发挥尚未明确的作用。成年心脏中AT2水平较低，而在心脏重塑过程中其分布比例增加，并且应用AT1拮抗剂可增强其作用。尽管在AT2基因敲除小鼠中对Ang II升压作用的敏感性增加，但其潜在机制仍不明确。在此，我们报告了一个意外发现，即使用α-肌球蛋白重链启动子在心脏特异性过表达AT2基因会导致对AT1介导的升压和变时作用的敏感性降低。在野生型小鼠心脏中无法检测到的AT2蛋白在AT2转基因（TG）小鼠的心房和心室中过表达，并且AT2相对于AT1的比例在心房中为41%，在心室中为45%。在心肌中未观察到明显的形态学变化，并且野生型和TG小鼠之间的心脏发育或心脏与体重比没有显著差异。向AT2 TG小鼠输注Ang II导致血压反应的增加明显减弱，并且这种变化被AT2拮抗剂预处理完全阻断。对Ang II诱导的升压作用敏感性降低主要是由于AT2介导的强烈负性变时作用，并且由循环中的Ang II在不刺激儿茶酚胺释放的生理范围内发挥作用。使用Langendorff装置灌注的AT2转基因小鼠的离体心脏对Ang II的变时反应也降低，对左心室dp/dt max值无影响，并且在转基因小鼠左心室中Ang II诱导的丝裂原活化蛋白激酶活性受到抑制。尽管在AT2 TG小鼠心肌细胞中记录的瞬时外向钾电流不受AT2激活的影响，但本研究表明AT2过表达降低了起搏细胞对Ang II的敏感性。我们的结果表明，刺激心脏AT2通过抑制AT1介导的变时作用发挥一种新的抗升压作用，并且对心血管疾病患者应用AT1拮抗剂具有刺激心脏AT2的有益药物治疗效果。
