Published Online
on April 11, 2005

A more recent version of this article appeared on May 1, 2005

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Submitted on February 8, 2005
Revised on February 23, 2005

The Antioxidant Edaravone Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy

Ikuko Tsujimoto; Shungo Hikoso; Osamu Yamaguchi; Kazunori Kashiwase; Atsuko Nakai; Toshihiro Takeda; Tetsuya Watanabe; Masayuki Taniike; Yasushi Matsumura; Kazuhiko Nishida; Masatsugu Hori; Mikihiko Kogo; and Kinya Otsu^*

From the Department of Internal Medicine and Therapeutics (I.T., S.H., O.Y., K.K., A.N., T.T., T.W., M.T., K.N., M.H., K.O.) and Department of Medical Information Science (Y.M.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan; and First Department of Oral and Maxillofacial Surgery (I.T., M.K.) and Department of Dental Anesthesiology (K.N.), Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: kotsu{at}medone.med.osaka-u.ac.jp.

Abstract--The free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) is used to treat patients with ischemic brain damage. We and others reported previously that in vitro and in vivo reactive oxygen species (ROS) act as second messengers to develop cardiac hypertrophy. In this study, we used an in vivo murine model of pressure overload-induced cardiac hypertrophy to examine the effects of edaravone on left ventricular hypertrophy. The animals were subjected to the transverse thoracic aorta constriction, and edaravone (10 mg/kg) was infused intraperitoneally twice daily. Seven days after the operation, we observed a significant increase in ROS production in hearts, which was eliminated by the treatment with edaravone. Pressure-overloaded hearts showed a significant increase in left ventricular weight/body weight ratio and the expression level of atrial natriuretic factor mRNA, which were attenuated by edaravone. It also reduced perivascular and intermuscular fibrosis and inhibited pressure overload-induced activation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream kinases of c-Jun N-terminal protein kinase and p38 mitogen-activated protein kinase. Edaravone attenuated the hypertrophic response even when the treatment was started after the onset of cardiac hypertrophic response. These findings indicate that edaravone significantly attenuates pressure overload-induced cardiac hypertrophy mediated through its antioxidative function and subsequent inhibition of ASK1 signaling pathway.

Key words: hypertrophy • oxidative stress • antioxidants • signal transduction • protein kinases • stress, mechanical

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