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Complement Protease MASP-1 Activates Human Endothelial Cells: PAR4 Activation Is a Link between Complement and Endothelial Function¹

Márton Megyeri^2,*, Veronika Makó^2,, László Beinrohr^*, Zoltán Doleschall, Zoltán Prohászka, László Cervenak, Péter Závodszky^* and Péter Gál^3,*

^* Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary; 3rd Department of Medicine, Semmelweis University, Budapest, Hungary; Department of Pathogenetics, National Institute of Oncology, Budapest, Hungary; and Research Group of Inflammation Biology and Immunogenomics, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary

Activation of the complement system can induce and enhance inflammatory reaction. Mannose-binding lectin-associated serine protease-1 (MASP-1) is an abundant protease of the complement lectin pathway; however, its physiological function is unclear. In this study, we demonstrate for the first time that MASP-1 is able to activate Ca²⁺ signaling, NF-B, and p38 MAPK pathways in cultured HUVECs. Activation was initiated by MASP-1 only; the related protease, MASP-2, had no such effect. The phenomenon was dependent on the proteolytic activity of MASP-1, suggesting modulation of endothelial cell function through a protease-activated receptor (PAR). Using synthetic peptide substrates representing the protease-sensitive regions of PARs, we were able to demonstrate that PAR4 is a target of MASP-1. The presence of functionally active PAR4 in HUVECs was demonstrated using PAR4 agonist peptide and mRNA quantification. Finally, we showed that the amount of membrane-bound intact PAR4 decreases after MASP-1 treatment. All of these results provide a novel link between the regulation of endothelial cell function and complement system activation, and they suggest that MASP-1-induced PAR4 activation could contribute to the development of the inflammatory reaction.

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 This work was supported by the Ányos Jedlik grant NKFP_07_1-MASPOK07 (NKTH, Hungarian National Office for Research and Technology) and by Grants NI61915, F67937, NK77978 (to P.Z.), and NF72689 (to Z.P.) (OTKA, Hungarian Scientific Research Fund).

² M.M. and V.M. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Péter Gál, Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, H-1113 Budapest, Karolina út 29, Hungary. E-mail address: gal{at}enzim.hu

⁴ Abbreviations used in this paper: MBL, mannose-binding lectin; C1-inh, C1 inhibitor; MASP, mannose-binding lectin-associated serine protease; PAR, protease-activated receptor.