AT2 receptor mediates the cardioprotective effects of AT1 receptor antagonist in post-myocardial infarction remodeling
AT2 receptor mediates the cardioprotective effects of AT1 receptor antagonist in post-myocardial infarction remodeling
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DOI：
10.1016/j.lfs.2006.08.033
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发表时间：
2006-12-03
期刊：
影响因子：
6.1
通讯作者：
Oshima, Tetsuya
中科院分区：
文献类型：
--
作者：
Oishi, Yoshihiko;Ozono, Ryoji;Oshima, Tetsuya
血管紧张素（Ang）II受体有两种亚型，即AT 1 R和AM。已确定临床使用特异性AT 1 R阻滞剂（ARB）可改善心力衰竭的长期预后。然而，对ARB这种作用的科学依据还不完全了解。本研究旨在确定ARB是否抑制心肌梗死（MI）后早期发生的左心室（LV）重塑，以及ARB的获益是否通过阻断AT 1 R本身或通过AT 1 R阻断引起的AT 2 R刺激介导。在AT 2 R敲除小鼠和野生型小鼠中诱导MI。手术后不久开始给予缬沙坦、ARB或溶媒，并持续两周。心肌梗死引起舒张末期和收缩末期左心室尺寸，左心室/体重比，和心肌细胞横截面积（MCSA）在两个菌株的显着增加到相似的程度。肺/体重比，肺充血的指数，也显着增加，在两个品系，但增加的幅度显着更大的基因敲除小鼠。缬沙坦显著降低野生型小鼠的LV尺寸、LV/体重比、MCSA和肺/体重比。然而，在基因敲除小鼠中，缬沙坦未能抑制LV尺寸和LV/体重比的增加。处理后，突变株小鼠的肺/体重比显著大于野生型小鼠。缬沙坦减轻急性期心肌梗死后重构，改善心力衰竭，其心肌保护作用很大一部分是通过AT 2 R介导的。(c)2006年爱思唯尔公司All rights reserved.
There are two subtypes of angiotensin (Ang) II receptors, AT1R and AM. It is established that clinical use of specific AT1R blocker (ARB) improves the long-term prognosis of heart failure. However, scientific basis for such effects of ARB is incompletely understood. The present study was designed to determine whether ARB inhibits the left ventricular (LV) remodeling that occurs early after myocardial infarction (MI) and whether the benefit of ARB is mediated by blockade of AT1R itself or by stimulation of AT2R resulting from AT1R blockade. MI was induced in AT2R-knockout mice and wild-type mice. Administration of valsartan, an ARB, or vehicle was started soon after the surgery and continued for two weeks. Infarction caused significant increase in end diastolic and end systolic LV dimensions, LV/body weight ratio, and myocyte cross-sectional area (MCSA) in both strains to a similar extent. Lung/body weight ratio, an index of pulmonary congestion, was also significantly increased in both strains, but the magnitude of increase was significantly larger in knockout mice. Valsartan significantly reduced LV dimensions, LV/body weight ratio, MCSA, and lung/body weight ratio in wild-type mice. In knockout mice, however, valsartan failed to inhibit the increases in LV dimensions and LV/body weight ratio. After the treatment, lung/body weight ratio in the mutant strain was significantly larger than that in the wild-type mice. Valsartan attenuates acute phase post-infarction remodeling and ameliorates heart failure, and a large part of its cardioprotective effect was mediated by AT2R. (c) 2006 Elsevier Inc. All rights reserved.