title: Association of RhoGDIalpha with Rac1 GTPase mediates free radical production during myocardial hypertrophy.
abstract: OBJECTIVE
  Reactive oxygen species (ROS) contribute to the pathogenesis of myocardial hypertrophy. NADPH oxidase is a major source of ROS production. The small GTPase Rac1 mediates the activation of NADPH oxidase; however, the mechanism of Rac1 activation is incompletely understood.
  
  
  RESULTS
  Transaortic constriction (TAC, C57/Bl6 mice, 360 microm, 21 days) increased the ratio of heart to body weight from [ per thousand] SHAM 4.16+/-0.09 to TAC 7.1+/-0.37, p<0.01. Treatment with rosuvastatin prevented pressure-induced cardiac hypertrophy (5.5+/-0.18, p<0.05). TAC induced a 4-fold up-regulation of myocardial NADPH oxidase activity as well as Rac1 activity; both effects were absent in statin-treated animals. In cultured rat cardiomyocytes, treatment with angiotensin II (AngII) increased translocation of Rac1 to cell membranes and Rac1 activity. AngII altered neither expression nor tyrosine phosphorylation of GTPase activating protein GAP-p190 and the guanine nucleotide exchange factors Vav and Tiam. Transaortic constriction as well as AngII increased the binding of Rho guanine nucleotide dissociation inhibitor (RhoGDIalpha) to Rac1. The association of RhoGDIalpha with Rac1 was mediated by phosphatidylinositol 3-kinase and depended on geranylgeranylation. Statin treatment inhibited RhoGDIalpha-Rac1 binding both in cultured cardiomyocytes and during myocardial hypertrophy in vivo. Transfection with RhoGDIalpha siRNA constructs potently reduced RhoGDIalpha protein expression, decreased AngII-induced superoxide production and lipid peroxidation, and inhibited AngII-induced leucine incorporation.
  
  
  CONCLUSIONS
  Myocardial hypertrophy is characterized by activation of Rac1 and NADPH oxidase. The association of the regulatory protein RhoGDIalpha with Rac1 represents a necessary step in the Rac1-dependent release of ROS. Rac1-RhoGDIalpha binding may represent a target for anti-hypertrophic pharmacologic interventions, potentially by statin treatment.
authors.affiliation: Klinik und Poliklinik für Innere Medizin III, Universität des Saarlandes, Homburg/Saar, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Custodis
authors.forename: Marcel
authors.initials: M
authors.lastname: Eberl
authors.forename: Heiko
authors.initials: H
authors.lastname: Kilter
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D006332:Cardiomegaly / Q000378:metabolism*; D002478:Cells, Cultured; D005464:Fluorobenzenes / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism*; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D047468:Immunoprecipitation; D007930:Leucine / Q000378:metabolism; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
chemical_list: C569639:Arhgdia protein, mouse; D005464:Fluorobenzenes; D005609:Free Radicals; D020730:Guanine Nucleotide Dissociation Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D013481:Superoxides; D000804:Angiotensin II; D000068718:Rosuvastatin Calcium; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; D007930:Leucine