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J. Biol. Chem., Vol. 279, Issue 48, 50120-50131, November 26, 2004

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ERK1/2 Regulates Intracellular ATP Levels through -Enolase Expression in Cardiomyocytes Exposed to Ischemic Hypoxia and Reoxygenation^*

Yoichi Mizukami¶, Akihiro Iwamatsu||, Toshihiko Aki, Masayasu Kimura**, Kazuyuki Nakamura, Tomoko Nao**, Tomoko Okusa**, Masunori Matsuzaki**, Ken-ichi Yoshida, and Sei Kobayashi

From the Center for Gene Research, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, the Department of Molecular Physiology, the ^**Department of Cardiovascular Medicine, and the Department of Biochemistry, Yamaguchi University School of Medicine, Yamaguchi 755-8505, the Department of Legal Medicine, Tokyo University School of Medicine, Tokyo 113-0033, and the ^||Central Laboratories for Key Technology, Kirin Brewery Co., Ltd., Kanagawa, Tokyo 236-0004, Japan

Extracellular signal-regulated kinase 1/2 (ERK1/2) is known to function in cell survival in response to various stresses; however, the mechanism of cell survival by ERK1/2 remains poorly elucidated in ischemic heart. Here we applied functional proteomics by two-dimensional electrophoresis to identify a cellular target of ERK1/2 in response to ischemic hypoxia. Approximately 1500 spots were detected by Coomassie Brilliant Blue staining of a sample from unstimulated cells. The staining intensities of at least 50 spots increased at 6-h reoxygenation after 2-h ischemic hypoxia. Of the 50 spots that increased, at least 4 spots were inhibited in the presence of PD98059, a MEK inhibitor. A protein with a molecular mass of 52 kDa that is strongly induced by ERK1/2 activation in response to ischemic hypoxia and reoxygenation was identified as -enolase, a rate-limiting enzyme in the glycolytic pathway, by liquid chromatography-mass spectrometry and amino acid sequencing. The expressions of the -enolase mRNA and protein are inhibited during reoxygenation after ischemic hypoxia in the cells containing a dominant negative mutant of MEK1 and treated with a MEK inhibitor, PD98059, leading to a decrease in ATP levels. -Enolase expression is also observed in rat heart subjected to ischemia-reperfusion. The induction of -enolase by ERK1/2 appears to be mediated by c-Myc. The introduction of the -enolase protein into the cells restores ATP levels and prevents cell death during ischemic hypoxia and reoxygenation in these cells. These results show that -enolase expression by ERK1/2 participates in the production of ATP during reoxygenation after ischemic hypoxia, and a decrease in ATP induces apoptotic cell death. Furthermore, -enolase improves the contractility of cardiomyocytes impaired by ischemic hypoxia. Our results reveal that ERK1/2 plays a role in the contractility of cardiomyocytes and cell survival through -enolase expression during ischemic hypoxia and reoxygenation.

Received for publication, March 1, 2004 , and in revised form, July 30, 2004.

^* This work was supported in part by grants from the Ministry of Education, Science and Culture of Japan, the Yamanouchi Foundation for Research on Metabolic Disorders, The Inamori Foundation, The Kowa Life Science Foundation, the Takeda Science Foundation, The Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Japan Heart Foundation Research Grant, the NOVARTIS Foundation (Japan) for the Promotion of Science, the Research Program for Special Promotion of the Venture Business Laboratory, Yamaguchi University, the Osaka Cancer Research Foundation, The Old Age Research Foundation of Yamaguchi, and the Yamaguchi Industrial Promotion Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 81-836-22-2183; Fax: 81-836-22-2185; E-mail: mizukami{at}yamaguchi-u.ac.jp.

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