Antagonism of Bradykinin B2 Receptor Prevents Inflammatory Responses in Human Endothelial Cells by Quenching the NF-kB Pathway Activation.docVIP

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Antagonism of Bradykinin B2 Receptor Prevents Inflammatory Responses in Human Endothelial Cells by Quenching the NF-kB Pathway Activation.doc

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Antagonism of Bradykinin B2 Receptor Prevents Inflammatory Responses in Human Endothelial Cells by Quenching the NF-kB Pathway Activation

AntagonismofBradykininB2ReceptorPrevents InflammatoryResponsesinHumanEndothelialCellsby QuenchingtheNF-kBPathwayActivation ErikaTerzuoli1,StefaniaMeini2,PaolaCucchi2,ClaudioCatalani2,CeciliaCialdai2,CarloAlbertoMaggi2, AntonioGiachetti1,MarinaZiche1*,SandraDonnini1* 1DepartmentofLifeSciences,UniversityofSiena,Siena,Italy?, 2PharmacologyDepartment,MenariniRicercheS.p.A,Florence,Italy Abstract Background:Bradykinin(BK)inducesangiogenesisbypromotingvesselpermeability,growthandremodeling.Thisstudy aimedtodemonstratethattheB2Rantagonist,fasitibant,inhibitstheBKpro-angiogeniceffects. Methodology:WeassesedtheabilityoffasibitanttoantagonizetheBKstimulationofculturedhumancells(HUVEC)and circulating pro-angiogenic cells (PACs), in producing cell permeability (paracellular flux), migration and pseocapillary formation.Thelatterparameterwasstudiedinvitro(matrigelassay)andinvivoinmice(matrigelplug)andinratmodelof experimentalosteoarthritis(OA).WealsoevaluatedNF-kBactivationinculturedcellsbymeasuringitsnucleartranslocation and its downstream effectors such as the proangiogenic ciclooxygenase-2 (COX-2), prostaglandin E-2 and vascular endothelialgrowthfactor(VEGF). Principalfindings:HUVEC,exposedtoBK(1–10mM),showedincreasedpermeability,disassemblyofadherensandtight- junction,increasedcellmigration,andpseudocapillariesformation.Weobservedasignificantincreaseofvesseldensityin the matrigel assay in mice and in rats OA model. Importantly, B2R stimulation elicited, both in HUVEC and PACs, NF-kB activation,leadingtoCOX-2overexpression,enhancedprostaglandinE-2production.andVEGFoutput.TheBK/NF-k Baxis, andtheensuingamplificationofinflammatory/angiogenicresponseswerefullypreventedbyfasitibantaswellasbyIKKVII, anNF-kB.Inhibitor. Conclusion:ThisworkillustratestheroleoftheendotheliumintheinflammationprovokedbytheBK/NF-kBaxis.Italso demonstates that B2R blockade by the antaogonist fasibitant, abolishes both the initial stimulus and its amplification, stronglyattenuatingthepropagationofinfl