TY - JOUR
T1 - Epoxycyclopentenone-containing oxidized phospholipids restore endothelial barrier function via Cdc42 and Rac
AU - Birukov, Konstantin G.
AU - Bochkov, Valery N.
AU - Birukova, Anna A.
AU - Kawkitinarong, Kamon
AU - Rios, Alexander
AU - Leitner, Alexander
AU - Verin, Alexander D.
AU - Bokoch, Gary M.
AU - Leitinger, Norbert
AU - Garcia, Joe G.N.
PY - 2004/10/29
Y1 - 2004/10/29
N2 - 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.
AB - 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.
KW - Actin cytoskeleton
KW - Endothelial permeability
KW - Mildly oxidized phospholipids
KW - Small GTPases
KW - Thrombin
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UR - http://www.scopus.com/inward/citedby.url?scp=7244239196&partnerID=8YFLogxK
U2 - 10.1161/01.RES.0000147310.18962.06
DO - 10.1161/01.RES.0000147310.18962.06
M3 - Article
C2 - 15472119
AN - SCOPUS:7244239196
SN - 0009-7330
VL - 95
SP - 892
EP - 901
JO - Circulation research
JF - Circulation research
IS - 9
ER -