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(Hypertension. 2007;50:926.)
© 2007 American Heart Association, Inc.

Original Articles

Novel Regulatory Effect of Angiotensin II Type 1 Receptor-Interacting Molecule on Vascular Smooth Muscle Cells

Koichi Azuma; Kouichi Tamura; Atsu-ichiro Shigenaga; Hiromichi Wakui; Shin-ichiro Masuda; Yuko Tsurumi-Ikeya; Yutaka Tanaka; Masashi Sakai; Miyuki Matsuda; Tatsuo Hashimoto; Tomoaki Ishigami; Marco Lopez-Ilasaca; Satoshi Umemura

From the Department of Cardiorenal Medicine (K.A., K.T., A.S., H.W., S.M., Y.T.-I., Y.T., M.S., M.M., T.H., T.I., S.U.), Yokohama City University School of Medicine, Yokohama, Japan; and the Department of Medicine (M.L.-I.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Kouichi Tamura, Department of Cardiorenal Medicine, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. E-mail tamukou{at}med.yokohama-cu.ac.jp

We have recently cloned a novel molecule that interacts with the angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP). In this study, we tested the hypothesis that ATRAP modulates angiotensin II-induced responses in vascular smooth muscle cells. The results of immunoprecipitation and bioluminescence resonance energy transfer assay demonstrated a direct interaction between ATRAP and AT1R at baseline and showed that angiotensin II enhanced the interaction of these proteins >2-fold. The results of immunofluorescence analysis also demonstrated that >65% of ATRAP constitutively colocalized with an endosome marker. Although only 36% of ATRAP colocalized with AT1R at baseline, angiotensin II enhanced the colocalization of these molecules and made 92% of ATRAP colocalize with AT1R on a quantitative fluorescence analysis. Overexpression of ATRAP by adenoviral transfer decreased the cell surface AT1R number from 4.33 to 2.13 fmol/10⁶ cells at baseline and from 3.04 to 1.26 fmol/10⁶ cells even after removal of angiotensin II. ATRAP also suppressed angiotensin II-mediated increases in c-fos gene transcription and transforming growth factor-ß production. Furthermore, this suppression was accompanied by inhibition of angiotensin II-induced activation of 5-bromodeoxyuridine incorporation. Finally, ATRAP knockdown by small-interference RNA activated angiotensin II-induced c-fos gene expression, which was effectively inhibited by valsartan, an AT1R-specific antagonist. These results indicate that ATRAP promotes internalization of AT1R and attenuates the angiotensin II-mediated c-fos-transforming growth factor-ß pathway and proliferative response in vascular smooth muscle cells, suggesting a novel strategy to inhibit vascular fibrosis and remodeling through a novel and specific blockade of AT1R signaling.

Key Words: angiotensin receptors • receptors • cell signaling • growth factors and cytokines • receptor internalization • renin-angiotensin system