Edaravone mimics sphingosine-1-phosphate-induced endothelial barrier enhancement in human microvascular endothelial cells.
Edaravone is a potent scavenger of hydroxyl radicals and is quite successful in patients with acute cerebral ischemia, and several organ-protective effects have been reported. Treatment of human microvascular endothelial cells with edaravone (1.5 microM) resulted in the enhancement of transmonolayer electrical resistance coincident with cortical actin enhancement and redistribution of focal adhesion proteins and adherens junction proteins to the cell periphery. Edaravone also induced small GTPase Rac activation and focal adhesion kinase (FAK; Tyr(576)) phosphorylation associated with sphingosine-1-phosphate receptor type 1 (S1P(1)) transactivation. S1P(1) protein depletion by the short interfering RNA technique completely abolished edaravone-induced FAK (Tyr(576)) phosphorylation and Rac activation. This is the first report of edaravone-induced endothelial barrier enhancement coincident with focal adhesion remodeling and cytoskeletal rearrangement associated with Rac activation via S1P(1) transactivation. Considering the well-established endothelial barrier-protective effect of S1P, endothelial barrier enhancement as a consequence of S1P(1) transactivation may at least partly be the potent mechanisms for the organ-protective effect of edaravone and is suggestive of edaravone as a therapeutic agent against systemic vascular barrier disorder.
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Kazuyoshi
K
Omori
Yasushi
Y
Shikata
Kei
K
Sarai
Naomi
N
Watanabe
Jun
J
Wada
Noriko
N
Goda
Noriyuki
N
Kataoka
Kenichi
K
Shikata
Hirofumi
H
Makino
D000199:Actins / Q000378:metabolism; D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D000077553:Edaravone; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D008833:Microcirculation / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013997:Time Factors; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D002317:Cardiovascular Agents; D016166:Free Radical Scavengers; D008246:Lysophospholipids; C496061:PXN protein, human; D051419:Paxillin; D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D020744:rac GTP-Binding Proteins; D013110:Sphingosine; D000077553:Edaravone; D000983:Antipyrine