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(Circulation. 2000;102:1996.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Calcineurin Inhibitor Attenuates the Development and Induces the Regression of Cardiac Hypertrophy in Rats With Salt-Sensitive Hypertension

Masaki Shimoyama, MD, PhD; Doubun Hayashi, MD; Yunzeng Zou, MD, PhD; Eiki Takimoto, MD; Miho Mizukami, MD; Koshiro Monzen, MD; Sumiyo Kudoh, MD, PhD; Yukio Hiroi, MD, PhD; Yoshio Yazaki, MD, PhD; Ryozo Nagai, MD, PhD; Issei Komuro, MD, PhD

From the Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Correspondence to Dr Issei Komuro, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail komuro-tky{at}umin.ac.jp

Background—It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet.

Methods and Results—In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg twice daily) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg twice daily but not with 0.01 mg/kg twice daily of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment.

Conclusions—These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.

Key Words: hypertrophy • hemodynamics • hypertension

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