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: Miki Kawai, Seinosuke Kawashima, Tsuyoshi Sakoda, Ryuji Toh, Akira Kikuchi, Keiko Yamauchi-Takihara, Keita Kunisada, Mitsuhiro Yokoyama
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 41 Issue 4 Pg. 956-62 (Apr 2003) ISSN: 1524-4563 [Electronic] United States
• PMID: 12642511 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Cytokines
• Proto-Oncogene Proteins c-fos
• RNA, Messenger
• ral Guanine Nucleotide Exchange Factor
• cardiotrophin 1
• Myosin Heavy Chains
• ral GTP-Binding Proteins
• ras Proteins

Topics

• Actins (genetics)
• Animals
• Cardiomegaly (etiology, metabolism)
• Cells, Cultured
• Cytokines (pharmacology)
• Mutation
• Myocytes, Cardiac (cytology, drug effects, 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, physiology)
• ral Guanine Nucleotide Exchange Factor (genetics, physiology)
• ras Proteins (metabolism)