Original ArticleOlmesartan Inhibits Cardiac Hypertrophy in Mice Overexpressing Renin Independently of Blood Pressure Its Beneficial Effects on ACE2/Ang(1–7)/Mas Axis and NADPH Oxidase ExpressionTanno, Tomohiro MD; Tomita, Hirofumi MD; Narita, Ikuyo MD; Kinjo, Takahiko MD; Nishizaki, Kimitaka MD; Ichikawa, Hiroaki MD; Kimura, Yoshihiro MD; Tanaka, Makoto PhD; Osanai, Tomohiro MD; Okumura, Ken MDAuthor Information Departments of *Cardiology; and †Hypertension and Stroke Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; and ‡Department of Health Promotion, Hirosaki University Graduate School of Health Sciences, Hirosaki, Japan. Reprints: Ken Okumura, MD, Department of Cardiology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan (e-mail: firstname.lastname@example.org). K. Okumura reports receiving remuneration from Daiichi-Sankyo. H. Tomita received research funding from Daiichi-Sankyo. The other authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org). Received August 27, 2015 Accepted January 19, 2016 Journal of Cardiovascular Pharmacology: June 2016 - Volume 67 - Issue 6 - p 503-509 doi: 10.1097/FJC.0000000000000374 Buy SDC Metrics Abstract Enhanced renin–angiotensin activity causes hypertension and cardiac hypertrophy. The angiotensin (Ang)-converting enzyme (ACE)2/Ang(1–7)/Mas axis pathway functions against Ang II type 1 receptor (AT1R) signaling. We investigated whether olmesartan (Olm), an AT1R blocker, inhibits cardiac hypertrophy independently of blood pressure, and evaluated the potential mechanisms. The 3- to 4-month-old male mice overexpressing renin in the liver (Ren-Tg) were given Olm (5 mg/kg/d) and hydralazine (Hyd) (3.5 mg/kg/d) orally for 2 months. Systolic blood pressure was higher in the Ren-Tg mice than in wild-type littermates. Olm and Hyd treatments lowered systolic blood pressure to the same degree. However, cardiac hypertrophy, evaluated by echocardiography, heart weight, cross-sectional area of cardiomyocytes, and gene expression, was inhibited by only Olm treatment, but not by Hyd. Olm treatment reversed decreased gene expressions of ACE2 and Mas receptor of Ren-Tg mice and inhibited enhanced NADPH oxidase (Nox)4 expression and reactive oxygen species, whereas Hyd treatment had no influence on them. These findings indicate that Olm treatment inhibits cardiac hypertrophy independently of blood pressure, not only through its original AT1R blockade but partly through enhancement of ACE2/Ang(1–7)/Mas axis and suppression of Nox4 expression. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.