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

Abstract

Abstract-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. (Hypertension. 2010;55:1157-1164.)Key Words: basic science Ⅲ receptors Ⅲ gene expression/regulation Ⅲ hypertrophy/remodeling Ⅲ angiotensin receptors E vidence suggests that the activation of angiotensin II (Ang II) type 1 receptor (AT 1 R) through the tissue renin-angiotensin system may play an important role in the development of cardiac hypertrophy. The carboxyl-terminal portion of AT 1 R is involved in the control of AT 1 R internalization independent of G protein coupling, and it plays an important role in linking receptor-mediated signal transduction to the specific biological response to Ang II. 1,2 We previously cloned a novel AT 1 R-associated protein (ATRAP) that specifically interacts with the carboxylterminal domain of AT 1 R. [3][4][5][6] We showed that ATRAP is broadly expressed in many tissues, as is AT 1 R, and suppresses Ang II-mediated pathological responses in cardiomyocytes and vascular smooth muscle cells by promoting the constitutive internalization of AT 1 R. 7-9 However, the function of ATRAP in cardiac hypertrophy in vivo still remains to be demonstrated. Thus, the present study was carried out to investigate whether there is a role for ATRAP in the cardiac hypertrophy induced by chronic Ang II ...

Prepubertal angiotensin blockade exerts long-term therapeutic effect through sustained ATRAP activation in salt-sensitive hypertensive rats

“…The characterization and specificity of the anti-ATRAP antibody and the anti-AT1R antibody (sc-1173; Santa Cruz Biotechnology Inc., Santa Cruz, California, USA) were described previously [19,20,25,26]. The antip22phox antibody (sc-20781; Santa Cruz Biotechnology Inc.), anti-p47phox antibody (sc-14015; Santa Cruz Biotechnology, Inc.), anti-Rac1 antibody (DAM1522857; Millipore) and anti-Ang II type 2 receptor (AT2R) antibody (sc-9040; Santa Cruz Biotechnology Inc.) were also used in this study.…”

“…The antip22phox antibody (sc-20781; Santa Cruz Biotechnology Inc.), anti-p47phox antibody (sc-14015; Santa Cruz Biotechnology, Inc.), anti-Rac1 antibody (DAM1522857; Millipore) and anti-Ang II type 2 receptor (AT2R) antibody (sc-9040; Santa Cruz Biotechnology Inc.) were also used in this study. Western blot analysis was performed essentially as described [19,20,25,26].…”

“…Real-time quantitative RT-PCR was performed by incubating the RT product with TaqMan Universal PCR Master Mix and a designed TaqMan probe (Applied Biosystems, Foster City, California, USA), essentially as described previously [20,26,28]. The RNA quantity was expressed relative to the 18S rRNA endogenous control.…”

A Single Initiating Cause of Hypertension; Potential for Primary Prevention

“…AT1r forms complexes with the C-terminal part of EGFR [58]. And, in the case of AT2r, it is proposed that structural similarities discussed previously favor a complex formulation with ECD of EGFR and that EGF binding (RapLo) initiates it.…”

14-3-3 protein and ATRAP bind to the soluble class IIB phosphatidylinositol transfer protein RdgBβ at distinct sites

“…Transgenic mice overexpressing ATRAP are protected against Ang II-induced cardiac hypertrophy [47] and after an inflammatory vascular injury [48]. On the other hand, ATRAP-deficient mice have increased arterial BP (blood pressure) and an expanded PV (plasma volume) [49].…”