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Ral GDP dissociation stimulator and Ral GTPase are involved in myocardial hypertrophy.
- Source :
-
Hypertension (Dallas, Tex. : 1979) [Hypertension] 2003 Apr; Vol. 41 (4), pp. 956-62. Date of Electronic Publication: 2003 Mar 17. - Publication Year :
- 2003
-
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.
- Subjects :
- Actins genetics
Animals
Cardiomegaly metabolism
Cells, Cultured
Cytokines pharmacology
Mutation
Myocytes, Cardiac cytology
Myocytes, Cardiac drug effects
Myocytes, Cardiac metabolism
Myosin Heavy Chains genetics
Promoter Regions, Genetic
Proto-Oncogene Proteins c-fos genetics
RNA, Messenger biosynthesis
Rats
Rats, Sprague-Dawley
Transcriptional Activation
Transfection
ral GTP-Binding Proteins genetics
ral Guanine Nucleotide Exchange Factor genetics
ras Proteins metabolism
Cardiomegaly etiology
ral GTP-Binding Proteins physiology
ral Guanine Nucleotide Exchange Factor physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4563
- Volume :
- 41
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Hypertension (Dallas, Tex. : 1979)
- Publication Type :
- Academic Journal
- Accession number :
- 12642511
- Full Text :
- https://doi.org/10.1161/01.HYP.0000063884.36641.63