This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 52/4/672    most recent HYPERTENSIONAHA.108.117341v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Shigenaga, A.-i. Articles by Umemura, S. Search for Related Content PubMed PubMed Citation Articles by Shigenaga, A.-i. Articles by Umemura, S. Related Collections Remodeling ACE/Angiotension receptors Cell signalling/signal transduction Gene expression Hypertension - basic studies Hypertrophy

(Hypertension. 2008;52:672.)
© 2008 American Heart Association, Inc.

Original Articles

Effect of Olmesartan on Tissue Expression Balance Between Angiotensin II Receptor and Its Inhibitory Binding Molecule

Atsu-ichiro Shigenaga; Kouichi Tamura; Hiromichi Wakui; Shin-ichiro Masuda; Koichi Azuma; Yuko Tsurumi-Ikeya; Motoko Ozawa; Masaki Mogi; Miyuki Matsuda; Kazuaki Uchino; Kazuo Kimura; Masatsugu Horiuchi; Satoshi Umemura

From the Department of Cardiorenal Medicine (A.S., K.T., H.W., S.M., K.A., Y.T.-I., M.O., M. Mogi, K.U., S.U.), Yokohama City University Graduate School of Medicine, Yokohama, Japan; the Department of Molecular Cardiovascular Biology and Pharmacology (M. Matsuda, M.H.), Ehime University, Graduate School of Medicine, Japan; and the Division of Cardiology (K.K.), Yokohama City University Medical Center, Yokohama, Japan.

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

We previously cloned a novel molecule interacting with angiotensin II (Ang II) type 1 receptor protein (ATRAP) and showed it to be an endogenous inhibitor of Ang II type 1 receptor signaling in cardiovascular cells. In this study, we tested a hypothesis that the balance of tissue expression of ATRAP and Ang II type 1 receptor is regulated in a tissue-specific manner during the development of hypertension and related cardiac hypertrophy. Concomitant with blood pressure increase and cardiac hypertrophy in spontaneously hypertensive rats, there was a constitutive decrease in the ratio of cardiac expression of ATRAP to Ang II type 1 receptor. However, treatment with olmesartan, an Ang II type 1 receptor–specific antagonist, either at a depressor or subdepressor dose, recovered the suppressed cardiac ATRAP to Ang II type 1 receptor ratio, which was accompanied by a decrease in Ang II type 1 receptor density, an inhibition of p38 mitogen-activated protein kinase activity, and a regression of cardiac hypertrophy. Furthermore, Ang II stimulation suppressed the ATRAP to Ang II type 1 receptor ratio with hypertrophic responses in both the cardiomyocytes and rat hearts. These findings show a tissue-specific regulatory balancing of the expression of ATRAP and Ang II type 1 receptor during the development of hypertension and cardiac remodeling and further suggest that the upregulation of the tissue ATRAP to Ang II type 1 receptor ratio may be one of the therapeutic benefits of olmesartan beyond its blood pressure-lowering effect.

Key Words: angiotensin II • angiotensin antagonists • angiotensin receptors • basic science • gene expression/regulation • hypertrophy/remodeling