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(Circulation. 2001;104:97.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Calcineurin Plays a Critical Role in the Development of Pressure Overload–Induced Cardiac Hypertrophy

Yunzeng Zou, MD, PhD; Yukio Hiroi, MD, PhD; Hiroki Uozumi, MD; Eiki Takimoto, MD; Haruhiro Toko, MD; Weidong Zhu, MD, PhD; Sumiyo Kudoh, MD, PhD; Miho Mizukami, MD; Masaki Shimoyama, MD, PhD; Futoshi Shibasaki, PhD; Ryozo Nagai, MD, PhD; Yoshio Yazaki, MD, PhD; Issei Komuro, MD, PhD

From the Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba (Y.Z., H.T., M.M., I.K.); the Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo (Y.H., H.U., E.T., W.Z., S.K., M.S., R.N.); Tokyo Metropolitan Institute of Medical Science, Tokyo (F.S.); and the International Medical Center of Japan, Tokyo (Y.Y.), Japan.

Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail komuro-tky{at}umin.ac.jp

Background—Although activation of the Ca²⁺-dependent phosphatase calcineurin has been reported to induce cardiomyocyte hypertrophy, whether calcineurin is involved in pressure overload–induced cardiac hypertrophy remains controversial.

Methods and Results—We examined in the present study the role of calcineurin in pressure overload–induced cardiac hypertrophy using transgenic mice that overexpress the dominant negative mutant of calcineurin specifically in the heart. There were no significant differences in body weight, blood pressure, heart rate, heart weight, and the cardiac calcineurin activity between the transgenic mice and their littermate wild-type mice at basal state. The activity of calcineurin was markedly increased by pressure overload produced by constriction of the abdominal aorta in the heart of wild-type mice but less increased in the heart of the transgenic mice. Pressure overload induced increases in heart weight, wall thickness of the left ventricle, and diameter of cardiomyocytes; reprogramming of expressions of immediate early response genes and fetal-type genes; activation of extracellular signal–regulated protein kinases; and fibrosis. All these hypertrophic responses were more prominent in the wild-type mice than in the transgenic mice.

Conclusions—These results suggest that calcineurin plays a critical role in the development of pressure overload–induced cardiac hypertrophy.

Key Words: calcineurin • hypertrophy • genes • pressure

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