Epoxycyclopentenone-containing oxidized phospholipids restore endothelial barrier function via Cdc42 and Rac.
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.
Birukov
Konstantin G
KG
Division of Pulmonary and Critical Care Medicine, Center for Translational Respiratory Medicine, Johns Hopkins University School of Medicine, Baltimore, Md, USA. kbirukov@jhmi.edu
Bochkov
Valery N
VN
Birukova
Anna A
AA
Kawkitinarong
Kamon
K
Rios
Alexander
A
Leitner
Alexander
A
Verin
Alexander D
AD
Bokoch
Gary M
GM
Leitinger
Norbert
N
Garcia
Joe G N
JG
D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D018076:DNA, Complementary / Q000235:genetics; D004134:Dimyristoylphosphatidylcholine / Q000494:pharmacology; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D028421:Isoprostanes / Q000302:isolation & purification / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D010084:Oxidation-Reduction; D010713:Phosphatidylcholines / Q000302:isolation & purification / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000166:cytology; D034741:RNA, Small Interfering / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000494:pharmacology; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
C500238:1-palmitoyl-2-(epoxycyclopentenone)-sn-glycero-3-phosphocholine; C500237:1-palmitoyl-2-(epoxyisoprostane-E2)-sn-glycero-3-phosphocholine; C468114:1-palmitoyl-2-arachidonyl-3-phosphorylcholine; D018076:DNA, Complementary; D028421:Isoprostanes; D008246:Lysophospholipids; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; D002084:Butylated Hydroxytoluene; C060506:sphingosine 1-phosphate; C055402:1-palmitoyl-2-linoleoylphosphatidylcholine; D013917:Thrombin; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D013110:Sphingosine; D004134:Dimyristoylphosphatidylcholine