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(Hypertension. 2003;41:956.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Ral GDP Dissociation Stimulator and Ral GTPase Are Involved in Myocardial Hypertrophy

Miki Kawai; Seinosuke Kawashima; Tsuyoshi Sakoda; Ryuji Toh; Akira Kikuchi; Keiko Yamauchi-Takihara; Keita Kunisada; Mitsuhiro Yokoyama

From the Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine (M.K., S.K., R.T., M.Y.), Kobe, Japan; the Department of Internal Medicine, Cardiovascular Division, Hyogo College of Medicine (T.S.), Hyogo, Japan; the Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University (A.K.), Hiroshima, Japan; and the Department of Molecular Medicine, Osaka University Graduate School of Medicine (K.K.), Osaka, Japan.

Correspondence to Seinosuke Kawashima, MD, Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail kawashim{at}med.kobe-u.ac.jp

Ras-related GTPase (Ral) is converted to the GTP-bound form by Ral GDP dissociation stimulator (Ral-GDS), a putative effector protein of Ras. Although a number of studies indicate that Ras induces cardiac hypertrophy, the functional role of Ral-GDS/Ral signaling pathway is as yet unknown in cardiac myocytes. We investigated the role of the Ral-GDS/Ral pathway in cardiac hypertrophy. Transfection of Ral-GDS and constitutively active mutant of Ral (RalG23V) in cultured rat neonatal myocytes stimulated promoter activity of c-fos (5.4-fold and 2.6-fold, P<0.01), -skeletal actin (2.7-fold and 2.1-fold, P<0.01), and ß-myosin heavy chain-luciferase (2.8-fold and 2.3-fold, P<0.01). Ral-GDS–induced or RalG23V-induced promoter activation was increased synergistically with activated Ras (RasG12V). Dominant-negative mutant of Ral (RalS28N) partially inhibited RasG12V induced promoter activation. Cardiac myocytes transfected with RalG23V showed increased cell size compared with nontransfected or vector-transfected cells (2.1-fold, P<0.01). Cardiotrophin-1 (CT-1) upregulated Ral-GDS mRNA expression and induced Ral activation. CT-1–induced Ral-GDS mRNA expression was inhibited by overexpression of the dominant-negative mutant of STAT3. Moreover, Ral activity was elevated in hypertrophied hearts (2.1-fold, P<0.01) by mechanical stress in association with increased CT-1 expression and signal transducer and activator of transcription 3 (STAT3) phosphorylation in the rat aortic banding model. Ral-GDS/Ral pathway is involved in a wide range of gene expressions and is activated by hypertrophic stimuli in vitro and in vivo. SATA3 may play a key role in Ral-GDS expression and Ral activation. Our data provide evidence that the Ral-GDS/Ral signaling pathway is a link to the process of cardiac hypertrophy.

Key Words: myocytes • hypertrophy • signal transduction • stress • gene expression

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