Submitted on October 10, 2006
Accepted on July 27, 2007
Edaravone mimics sphingosine 1-phosphate-induced endothelial barrier enhancement in human microvascular endothelial cells
Kazuyoshi Omori1*, Yasushi Shikata1, Kei Sarai1, Naomi Watanabe1, Jun Wada1, Noriko Goda2, Noriyuki Kataoka3, Kenichi Shikata1, and Hirofumi Makino1
1 Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
2 Faculty of Health Sciences, Okayama University Medical School, Okayama, Japan
3 Department of Medical Engineering, Kawasaki Medical School, Okayama, Japan
* To whom correspondence should be addressed. E-mail: kaz197669{at}yahoo.co.jp.
Edaravone is a potent scavenger of hydroxyl radicals, 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) [Y576] phosphorylation associated with sphingosine 1-phosphate receptor type 1 (S1P1) transactivation. S1P1 protein depletion by siRNA technique completely abolished edaravone-induced FAK [Y576] 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 S1P1 transactivation. Considering the well-established endothelial barrier protective effect of S1P, endothelial barrier enhancement as a consequence of S1P1 transactivation may at least partly be the potent mechanisms for the organ protective effect of edaravone, suggestive of edaravone as a therapeutic agent against systemic vascular barrier disorder.
