Clin Res Cardiol 98, Suppl 1, April 2009

V237 - Inhibition of rac-1 GTPase decreases vascular oxidative stress, improves endothelial function and attenuates atherosclerosis development in mice
 
S. Zimmer1, C. Müller1, I. Paez-Maletz1, U. Laufs2, K. Aktories3, G. Nickenig1, S. Waßmann1
 
1Inn. Med. m. S. Kardiologie, Pneumologie, Universitätsklinikum Bonn - Med. Klinik u. Poliklinik II, Bonn; 2Innere Medizin III, Kardiologie und Angiologie, Universitätsklinikum des Saarlandes, Homburg/Saar; 3Institut für exp. u. klin. Pharmakologie u. Toxikologie, Universität Freiburg, Freiburg im Breisgau;
 
Background: Oxidative stress and inflammation contribute to the pathogenesis of atherosclerosis. Rac-1 GTPase, a member of the rho family of small GTPases, regulates NADPH oxidase activity and thus reactive oxygen species (ROS) formation. It also modulates actin cytoskeleton and monocyte adhesion. We investigated the effects of rac-1 inhibition in wild-type and apolipoprotein E-deficient (ApoE-/-) mice.
Methods and Results: Wild-type mice treated via osmotic mini-pumps for 7d with Clostridium sordellii lethal toxin (LT), a specific rac-1 inhibitor, displayed decreased vascular ROS production (L-012 chemiluminescence) and NADPH oxidase activity (lucigenin-enhanced chemiluminescence). To investigate whether rac-1 inhibition has an impact on endothelial dysfunction, ApoE-/- mice were fed a cholesterol-rich diet for 7 weeks and were treated with LT or vehicle for the last 7d. ApoE-/- mice showed endothelial dysfunction, as indicated by an impaired endothelium-dependent vasodilation (organ chamber experiments with isolated aortic segments), which was improved by treatment with LT. To investigate the effect on atherosclerosis development, ApoE-/- mice were fed a cholesterol-rich diet for 7 weeks and were concomitantly treated with LT or vehicle. Chronic LT treatment led to decreased aortic rac-1 activity (GST-PAK pull-down assays), ROS production and NADPH oxidase activity. This was accompanied by attenuation of atherosclerotic lesion formation in the aortic root (oil-red staining) and reduced macrophage infiltration of the atherosclerotic plaques (immunohistochemistry).
Conclusions: Inhibition of rac-1 GTPase decreases vascular NADPH oxidase activity and oxidative stress in vivo, improves endothelial function and attenuates atherosclerosis development in mice.
 

http://www.abstractserver.de/dgk2009/ft/abstracts/V237.htm