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Association of RhoGDIα with Rac1 GTPase mediates free radical production during myocardial hypertrophy

Authors :
Custodis, Florian
Eberl, Marcel
Kilter, Heiko
Böhm, Michael
Laufs, Ulrich
Source :
Cardiovascular Research. Jul2006, Vol. 71 Issue 2, p342-351. 10p.
Publication Year :
2006

Abstract

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. Methods and results: Transaortic constriction (TAC, C57/Bl6 mice, 360 μm, 21 days) increased the ratio of heart to body weight from [‰] 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 (RhoGDIα) to Rac1. The association of RhoGDIα with Rac1 was mediated by phosphatidylinositol 3-kinase and depended on geranylgeranylation. Statin treatment inhibited RhoGDIα–Rac1 binding both in cultured cardiomyocytes and during myocardial hypertrophy in vivo. Transfection with RhoGDIα siRNA constructs potently reduced RhoGDIα 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 RhoGDIα with Rac1 represents a necessary step in the Rac1-dependent release of ROS. Rac1–RhoGDIα binding may represent a target for anti-hypertrophic pharmacologic interventions, potentially by statin treatment. [Copyright &y& Elsevier]

Details

Language :
English
ISSN :
00086363
Volume :
71
Issue :
2
Database :
Academic Search Index
Journal :
Cardiovascular Research
Publication Type :
Academic Journal
Accession number :
21340583
Full Text :
https://doi.org/10.1016/j.cardiores.2006.04.005