Ral GDP dissociation stimulator and Ral GTPase are involved in myocardial hypertrophy

Hypertension. 2003 Apr;41(4):956-62. doi: 10.1161/01.HYP.0000063884.36641.63. Epub 2003 Mar 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Animals
  • Cardiomegaly / etiology*
  • 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 GTP-Binding Proteins / physiology*
  • ral Guanine Nucleotide Exchange Factor / genetics
  • ral Guanine Nucleotide Exchange Factor / physiology*
  • ras Proteins / metabolism

Substances

  • 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