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(Circulation Research. 2004;95:892.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Epoxycyclopentenone-Containing Oxidized Phospholipids Restore Endothelial Barrier Function via Cdc42 and Rac

Konstantin G. Birukov, Valery N. Bochkov, Anna A. Birukova, Kamon Kawkitinarong, Alexander Rios, Alexander Leitner, Alexander D. Verin, Gary M. Bokoch, Norbert Leitinger, Joe. G.N. Garcia

From the Division of Pulmonary and Critical Care Medicine (K.G.B., A.A.B., K.K., A.R., A.D.V., J.G.N.G.), Center for Translational Respiratory Medicine, Johns Hopkins University School of Medicine, Baltimore, Md; Departments of Vascular Biology and Thrombosis Research (V.N.B., N.L.) and Analytical Chemistry (A.L.), University of Vienna, Vienna, Austria; and Department of Cell Biology (G.M.B.), The Scripps Research Institute, La Jolla, Calif.

Correspondence to Konstantin G. Birukov, 5200 Eastern Ave, MFL Center Tower, 677, Baltimore, MD 21224. E-mail kbirukov{at}jhmi.edu

After an acute phase of inflammation or injury, restoration of the endothelial barrier is important to regain vascular integrity and to prevent edema formation. However, little is known about mediators that control restoration of endothelial barrier function. We show here that oxidized phospholipids that accumulate at sites of inflammation and tissue damage are potent regulators of endothelial barrier function. Oxygenated epoxyisoprostane-containing phospholipids, but not fragmented oxidized phospholipids, exhibited barrier-protective effects mediated by small GTPases Cdc42 and Rac and their cytoskeletal, focal adhesion, and adherens junction effector proteins. Oxidized phospholipid-induced cytoskeletal rearrangements resulted in a unique peripheral actin rim formation, which was mimicked by coexpression of constitutively active Cdc42 and Rac, and abolished by coexpression of dominant-negative Rac and Cdc42. Thus, oxidative modification of phospholipids during inflammation leads to the formation of novel regulators that may be critically involved in restoration of vascular barrier function.

Key Words: endothelial permeability • mildly oxidized phospholipids • small GTPases • actin cytoskeleton • thrombin

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