title: Ral GDP dissociation stimulator and Ral GTPase are involved in myocardial hypertrophy.
abstract: 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), alpha-skeletal actin (2.7-fold and 2.1-fold, P<0.01), and beta-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.
authors.affiliation: 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.
authors.forename: Miki
authors.initials: M
authors.lastname: Kawai
authors.forename: Seinosuke
authors.initials: S
authors.lastname: Kawashima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Sakoda
authors.forename: Ryuji
authors.initials: R
authors.lastname: Toh
authors.forename: Akira
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamauchi-Takihara
authors.forename: Keita
authors.initials: K
authors.lastname: Kunisada
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yokoyama
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation; D014162:Transfection; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020726:ral Guanine Nucleotide Exchange Factor / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D016207:Cytokines; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D020726:ral Guanine Nucleotide Exchange Factor; C092073:cardiotrophin 1; D018995:Myosin Heavy Chains; D020725:ral GTP-Binding Proteins; D018631:ras Proteins