Agonist-Independent Constitutive Activity of Angiotensin II Receptor Promotes Cardiac Remodeling in Mice
Agonist-Independent Constitutive Activity of Angiotensin II Receptor Promotes Cardiac Remodeling in Mice
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DOI：
10.1161/hypertensionaha.111.175208
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发表时间：
2012-03
期刊：
影响因子：
8.3
通讯作者：
N. Yasuda;H. Akazawa;K. Ito;I. Shimizu;Yoko Kudo-Sakamoto;Chizuru Yabumoto;M. Yano;R. Yamamoto;Yukako Ozasa;T. Minamino;A. Naito;T. Oka;I. Shiojima;K. Tamura;S. Umemura;P. Paradis;M. Nemer;I. Komuro
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文献类型：
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作者：
N. Yasuda;H. Akazawa;K. Ito;I. Shimizu;Yoko Kudo-Sakamoto;Chizuru Yabumoto;M. Yano;R. Yamamoto;Yukako Ozasa;T. Minamino;A. Naito;T. Oka;I. Shiojima;K. Tamura;S. Umemura;P. Paradis;M. Nemer;I. Komuro
血管紧张素II (Ang II) 1型（AT1）受体主要介导Ang II的生理和病理作用，但最近的研究表明，即使在培养细胞中没有Ang II， AT1受体也固有地表现出自发的构成活性。为了阐明不依赖于Ang ii的AT1受体激活在心脏重构发病机制中的作用，我们在血管紧张素原敲除背景下，在-myosin重链启动子的控制下，构建了过表达AT1受体的转基因小鼠（AT1Tg-AgtKO小鼠）。在AT1Tg-AgtKO心脏中，与血管紧张素原敲除小鼠心脏相比，Gq11亚基在细胞质中的重新分布和细胞外信号调节激酶的磷酸化显著增加，这表明AT1受体是独立于Ang II的组成性激活。结果，AT1Tg-AgtKO小鼠表现出自发性收缩功能障碍和腔室扩张，并伴有严重的间质纤维化。用坎地沙坦治疗AT1Tg-AgtKO小鼠心脏重构的进展可以被阻止，坎地沙坦是一种AT1受体的逆激动剂，但它的衍生物坎地沙坦- 7h却不能，由于缺乏苯并咪唑环上的羧基，坎地沙坦- 7h缺乏逆激动作用。我们的研究结果表明，即使在没有Ang II的情况下，当AT1受体在心脏中上调时，AT1受体在基础条件下的组成活性也有助于心脏重塑。
The angiotensin II (Ang II) type 1 (AT1) receptor mainly mediates the physiological and pathological actions of Ang II, but recent studies have suggested that AT1 receptor inherently shows spontaneous constitutive activity even in the absence of Ang II in culture cells. To elucidate the role of Ang II–independent AT1 receptor activation in the pathogenesis of cardiac remodeling, we generated transgenic mice overexpressing AT1 receptor under the control of -myosin heavy chain promoter in angiotensinogen-knockout background (AT1Tg-AgtKO mice). In AT1Tg-AgtKO hearts, redistributions of the Gq11 subunit into cytosol and phosphorylation of extracellular signal-regulated kinases were significantly increased, compared with angiotensinogen-knockout mice hearts, suggesting that the AT1 receptor is constitutively activated independent of Ang II. As a consequence, AT1Tg-AgtKO mice showed spontaneous systolic dysfunction and chamber dilatation, accompanied by severe interstitial fibrosis. Progression of cardiac remodeling in AT1Tg-AgtKO mice was prevented by treatment with candesartan, an inverse agonist for the AT1 receptor, but not by its derivative candesartan-7H, deficient of inverse agonism attributed to a lack of the carboxyl group at the benzimidazole ring. Our results demonstrate that constitutive activity of the AT1 receptor under basal conditions contributes to the cardiac remodeling even in the absence of Ang II, when the AT1 receptor is upregulated in the heart.