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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1744.)
© 2005 American Heart Association, Inc.

Thrombosis

Mast Cell–Derived Exosomes Activate Endothelial Cells to Secrete Plasminogen Activator Inhibitor Type 1

Khalid Al-Nedawi; Janusz Szemraj; Czeslaw S. Cierniewski

From the Center of Medical Biology (K.A.-N., C.S.C.), Polish Academy of Sciences, Department of Biochemistry (J.S.), and Department of Medical and Biological Biophysics (C.S.C.), Medical University in Lodz, Poland.

Correspondence to Czeslaw S. Cierniewski, PhD, Department of Medical and Molecular Biophysics, Medical University in Lodz, 92-213 Lodz, 6/8 Mazowiecka Street, Lodz, Poland. E-mail cciern{at}zdn.am.lodz.pl

Objective— Previous studies supported the contribution of exosomes to an acellular mode of communication, leading to intercellular transfer of molecules. In this study we provide evidence that mast cell-derived exosomes induce plasminogen activator inhibitor type 1 (PAI-1) expression in endothelial cells, detectable at the level of PAI-1 mRNA and protein synthesis. The stimulating effect was also measured at the level of PAI-1 promoter activity.

Methods and Results— To identify components responsible for this activity, exosome proteins were separated by 2-dimensional PAGE, and protein spots were identified by microsequencing using electrospray (ISI-Q-TOF-Micromass) spectrometer. Components of 3 independent systems that can be involved in activation of endothelial cells, namely the prothrombinase complex, tumor necrosis factor-, and angiotensinogen precursors were identified. Procoagulant activity of exosomes was confirmed by a thrombin generation assay using a specific chromogenic substrate. Because the potential of mast cell-derived exosomes to induce PAI-1 expression was completely abolished by hirudin, thrombin generated on exosomes seems to be responsible for this activity.

Conclusions— It can be concluded that mast cell-derived exosomes via significant upregulation of PAI-1 secretion from endothelial cells may provide feedback between the characteristically increased PAI-1 levels and procoagulant states, both observed in diverse syndromes manifesting as endothelial cell dysfunction.

We showed that mast cell-derived exosomes induce PAI-1 expression in endothelial cells. Proteomic analysis of exosomes identified components of the prothrombinase complex that after activation are responsible for upregulation of PAI-1.

Key Words: exosomes • mast cells • plasminogen activator inhibitor type 1 • prothrombinase complex

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