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J. Biol. Chem., Vol. 281, Issue 2, 1066-1072, January 13, 2006

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Binding of PAI-1 to Endothelial Cells Stimulated by Thymosin 4 and Modulation of Their Fibrinolytic Potential^*

Joanna Boncela, Katarzyna Smolarczyk, Elzbieta Wyroba, and Czeslaw S. Cierniewski¶1

From the Center of Medical Biology, Polish Academy of Sciences, 93-232 Lodz, The Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, and the ^¶Department of Molecular and Medical Biophysics, Medical University in Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, Poland

Our previous studies showed that thymosin 4 (T4) induced the synthesis of plasminogen activator inhibitor-1 (PAI-1) in cultured human umbilical vein endothelial cells (HUVECs) via the AP-1 dependent mechanism and its enhanced secretion. In this work we provide evidence that the released PAI-1 is accumulated on the surface of HUVECs, exclusively in its active form, in a complex with 1-acid glycoprotein (AGP) that is also up-regulated and released from the cells. This mechanism is supported by several lines of experiments, in which expression of both proteins was analyzed by flow cytometry and their colocalization supported by confocal microscopy. PAI-1 did not bind to quiescent cells but only to the T4-activated endothelial cells. In contrast, significant amounts of AGP were found to be associated with the cells overexpressing enhanced green fluorescent protein (EGFP)-1-acid glycoprotein (AGP) without T4 treatment. The AGP·PAI-1 complex was accumulated essentially at the basal surface of endothelial cells, and such cells showed (a) morphology characteristic for strongly adhered and spread cells and (b) significantly reduced plasmin formation. Taken together, these results provide the evidence supporting a novel mechanism by which active PAI-1 can be bound to the T4-activated endothelial cells, thus influencing their adhesive properties as well as their ability to generate plasmin.

Received for publication, June 9, 2005 , and in revised form, November 4, 2005.

^* This work was supported by Projects 3/PO4A 068 23 and PBZ-KBN-107/P04/2004 from the Polish Ministry of Scientific Research and Information Technology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 48-42-6783393; E-mail: cciern{at}zdn.am.lodz.pl.

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