Cardiac-Specific Activation of Angiotensin II Type 1 Receptor–Associated Protein Completely Suppresses Cardiac Hypertrophy in Chronic Angiotensin II

DOI：

10.1161/hypertensionaha.109.147207

发表时间：

2010-05

期刊：

Hypertension

影响因子：

8.3

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

H. Wakui;K. Tamura;Yutaka Tanaka;M. Matsuda;Y. Bai;Toru Dejima;Shin-ichiro Masuda;Atsu-ichiro Shigenaga;Akinobu Maeda;M. Mogi;Naoaki Ichihara;Yusuke Kobayashi;N. Hirawa;T. Ishigami;Y. Toya;M. Yabana;M. Horiuchi;S. Minamisawa;S. Umemura

我们克隆了一个与血管紧张素II型1受体相互作用的新分子，我们将其命名为ATRAP（血管紧张素II型1受体相关蛋白）。先前的体外研究表明，ATRAP显著促进血管紧张素II型1受体的组成性内化，并进一步减弱血管紧张素II介导的心肌细胞肥厚反应。本研究旨在探讨ATRAP在血管紧张素II输注心脏肥厚中的可能功能作用。我们首先检测了血管紧张素II输注对C57BL/6J野生型小鼠心脏内源性ATRAP表达的影响。血管紧张素II治疗促进心脏肥厚，同时心脏ATRAP表达显著降低，但心脏血管紧张素II型1受体表达无显著变化。我们假设心脏ATRAP对血管紧张素II型1受体比例的下调参与了心脏肥厚的发病机制。为了验证这一假设，我们接下来在-肌球蛋白重链启动子的控制下，在心肌细胞中产生特异性表达ATRAP的转基因小鼠。在心脏特异性ATRAP转基因小鼠中，血管紧张素II处理下，心肌肥厚的发生、p38丝裂原活化蛋白激酶的激活以及肥厚相关基因的表达均被完全抑制，尽管转基因小鼠与同卵对照小鼠的血压在无线电遥测中没有显著差异。这些结果表明，ATRAP在体内的心肌细胞特异性过表达可消除慢性血管紧张素II输注引起的心脏肥厚，从而提示ATRAP可能是心脏肥厚的新治疗靶点。

We cloned a novel molecule interacting with angiotensin II type 1 receptor, which we named ATRAP (for angiotensin II type 1 receptor–associated protein). Previous in vitro studies showed that ATRAP significantly promotes constitutive internalization of the angiotensin II type 1 receptor and further attenuates angiotensin II–mediated hypertrophic responses in cardiomyocytes. The present study was designed to investigate the putative functional role of ATRAP in cardiac hypertrophy by angiotensin II infusion in vivo. We first examined the effect of angiotensin II infusion on endogenous ATRAP expression in the heart of C57BL/6J wild-type mice. The angiotensin II treatment promoted cardiac hypertrophy, concomitant with a significant decrease in cardiac ATRAP expression, but without significant change in cardiac angiotensin II type 1 receptor expression. We hypothesized that a downregulation of the cardiac ATRAP to angiotensin II type 1 receptor ratio is involved in the pathogenesis of cardiac hypertrophy. To examine this hypothesis, we next generated transgenic mice expressing ATRAP specifically in cardiomyocytes under control of the -myosin heavy chain promoter. In cardiac-specific ATRAP transgenic mice, the development of cardiac hypertrophy, activation of p38 mitogen-activated protein kinase, and expression of hypertrophy-related genes in the context of angiotensin II treatment were completely suppressed, in spite of there being no significant difference in blood pressure on radiotelemetry between the transgenic mice and littermate control mice. These results demonstrate that cardiomyocyte-specific overexpression of ATRAP in vivo abolishes the cardiac hypertrophy provoked by chronic angiotensin II infusion, thereby suggesting ATRAP to be a novel therapeutic target in cardiac hypertrophy.

Cardiac-Specific Activation of Angiotensin II Type 1 Receptor–Associated Protein Completely Suppresses Cardiac Hypertrophy in Chronic Angiotensin II–Infused Mice

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