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

作者：Custodis Florian; Eberl Marcel; Kilter Heiko; Boehm Michael; Laufs Ulrich^*

来源：Cardiovascular Research, 2006, 71(2): 342-351.

DOI：10.1016/j.cardiores.2006.04.005

• hypertrophy
• oxygen radicals
• NADPH oxidase
• statins
• myocytes

Objective: Reactive oxygen species (ROS) contribute to the pathogenesis of myocardial hypertrophy. NADPH oxidase is a major source of ROS production. The small GTPase Racl mediates the activation of NADPH oxidase; however, the mechanism of Racl activation is incompletely understood.
Methods and results: Transaortic constriction (TAC, C57/B16 mice, 360 gm, 21 days) increased the ratio of heart to body weight from [parts 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 Racl activity; both effects were absent in statin-treated animals. In cultured rat cardiomyocytes, treatment with angiotensin II (AngII) increased translocation of Racl to cell membranes and Racl 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 (RhoGDI alpha) to Racl. The association of RhoGDIa with Racl was mediated by phosphatidylinositol 3-kinase and depended on geranylgeranylation. Statin treatment inhibited RhoGDI alpha-Rac1 binding both in cultured cardiomyocytes and during myocardial hypertrophy in vivo. Transfection with RhoGDIa siRNA constructs potently reduced RhoGDIa protein expression, decreased AngII-induced superoxide production and lipid peroxidation, and inhibited AngII-induced leucine incorporation.
Conclusions: Myocardial hypertrophy is characterized by activation of RacI and NADPH oxidase. The association of the regulatory protein RhoGDIa with Racl represents a necessary step in the Rac1-dependent release of ROS. Rac1-RhoGDI alpha binding may represent a target for anti-hypertrophic pharmacologic interventions, potentially by statin treatment.

• 出版日期2006-7-15