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(Hypertension. 2009;54:164.)
© 2009 American Heart Association, Inc.

Original Articles

Chymase Plays an Important Role in Left Ventricular Remodeling Induced by Intermittent Hypoxia in Mice

Chika Matsumoto; Tetsuya Hayashi; Kento Kitada; Chika Yamashita; Masatoshi Miyamura; Tatsuhiko Mori; Akira Ukimura; Mamoru Ohkita; Denan Jin; Shinji Takai; Mizuo Miyazaki; Yoshikatsu Okada; Yasushi Kitaura; Yasuo Matsumura

From the Laboratory of Pathological and Molecular Pharmacology (C.M., K.K., C.Y., M.O., Y.M.), Osaka University of Pharmaceutical Sciences; and the Departments of Internal Medicine III (T.H., M. Miyamura, T.M., A.U., Y.K.), Pharmacology (D.J., S.T., M. Miyazaki), and Pathology (Y.O.), Osaka Medical College, Takatsuki, Osaka, Japan.

Correspondence to Tetsuya Hayashi, Department of Internal Medicine III, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan. E-mail in3015{at}poh.osaka-med.ac.jp

Intermittent hypoxia caused by sleep apnea is associated with cardiovascular disease. Chymase has been reported to play an important role in the development of cardiovascular disease, but it is unclear whether chymase is involved in the pathogenesis of left ventricular remodeling induced by intermittent hypoxia. The aim of this study was to evaluate the effect of a novel chymase inhibitor (NK3201) on hypoxia-induced left ventricular remodeling in mice. Male C57BL/6J mice (9 weeks old) were exposed to intermittent hypoxia or normoxia and were treated with NK3201 (10 mg/kg per day) or the vehicle for 10 days. Left ventricular systolic pressure showed no significant differences among all of the experimental groups. Exposure to intermittent hypoxia increased left ventricular chymase activity and angiotensin II expression, which were both suppressed by treatment with NK3201. Intermittent hypoxia also increased the mean cardiomyocyte diameter, perivascular fibrosis, expression of inflammatory cytokines, oxidative stress, and NADPH-dependent superoxide production in the left ventricular myocardium. These changes were all suppressed by NK3201 treatment. Therefore, chymase might play an important role in intermittent hypoxia-induced left ventricular remodeling, which is independent of the systemic blood pressure.

Key Words: sleep apnea • hypoxia • chymase • cardiac remodeling • oxidative stress