Medizinische Klinik und Poliklinik II, University of Bonn, Germany.
J Mol Cell Cardiol. 2012 Mar;52(3):630-7. doi: 10.1016/j.yjmcc.2011.12.007. Epub 2011 Dec 22.
AT1 receptor blockers (ARB) and in part ACE inhibitors (ACI) potentially exert beneficial effects on atherogenesis independent of AT1 receptor inhibition. These pleiotropic effects might be related to angiotensin II mediated activation of the AT2 receptor. To analyze this hypothesis we investigated the development of atherosclerosis and the role of ACIs and ARBs in apolipoprotein E-deficient (ApoE(-/-)) mice and in ApoE/AT1A receptor double knockout mice (ApoE(-/-)/AT1A(-/-)). ApoE(-/-) mice and ApoE(-/-)/AT1A(-/-) mice were fed cholesterol-rich diet for 7 weeks. Vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation were evident in ApoE(-/-) mice, but were markedly reduced in ApoE(-/-)/AT1A(-/-) mice. Concomitant treatment of ApoE(-/-)/AT1A(-/-) mice with either telmisartan or ramipril had no additional effect on blood pressure, vascular oxidative stress, AT2 receptor expression, and endothelial function. Remarkably, atherosclerotic lesion formation was increased in ramipril treated ApoE(-/-)/AT1A(-/-) mice compared to untreated ApoE(-/-)/AT1A(-/-) mice whereas pharmacological AT1 receptor inhibition with telmisartan had no additional effect on atherogenesis. Moreover, chronic AT2 receptor inhibition with PD123,319 significantly increased plaque development in ApoE(-/-)/AT1A(-/-) mice. In additional experiments, direct AT2 receptor stimulation reduced atherogenesis in ApoE(-/-)/AT1A(-/-) mice. Taken together, our data demonstrate a relevant antiatherosclerotic role of the AT2 receptor in atherosclerotic mice and provide novel insight in RAS-physiology.
血管紧张素受体阻滞剂（ARB）和部分血管紧张素转换酶抑制剂（ACEI）除了通过阻断 AT1 受体外，还可能对动脉粥样硬化形成产生有益影响。这些多效作用可能与血管紧张素 II 介导的 AT2 受体激活有关。为了分析这一假说，我们研究了动脉粥样硬化的发生以及 ACEI 和 ARB 在载脂蛋白 E 缺陷（ApoE(-/-)）小鼠和 ApoE/AT1A 受体双敲除（ApoE(-/-)/AT1A(-/-)）小鼠中的作用。用富含胆固醇的饮食喂养 ApoE(-/-)小鼠和 ApoE(-/-)/AT1A(-/-)小鼠 7 周。ApoE(-/-)小鼠的血管氧化应激、内皮功能障碍和动脉粥样硬化病变形成明显，而 ApoE(-/-)/AT1A(-/-)小鼠则明显减少。同时用替米沙坦或雷米普利治疗 ApoE(-/-)/AT1A(-/-)小鼠对血压、血管氧化应激、AT2 受体表达和内皮功能没有额外影响。值得注意的是，与未治疗的 ApoE(-/-)/AT1A(-/-)小鼠相比，雷米普利治疗的 ApoE(-/-)/AT1A(-/-)小鼠的动脉粥样硬化病变形成增加，而替米沙坦对动脉粥样硬化形成的药理学 AT1 受体抑制则没有额外影响。此外，PD123,319 慢性 AT2 受体抑制显著增加了 ApoE(-/-)/AT1A(-/-)小鼠的斑块形成。在额外的实验中，直接刺激 AT2 受体可减少 ApoE(-/-)/AT1A(-/-)小鼠的动脉粥样硬化形成。综上所述，我们的数据表明 AT2 受体在动脉粥样硬化小鼠中具有重要的抗动脉粥样硬化作用，并为 RAS 生理学提供了新的见解。
