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dc.contributor.advisorHansen, John-Bjarne
dc.contributor.authorSovershaev, Timofey
dc.date.accessioned2016-12-20T09:37:59Z
dc.date.available2016-12-20T09:37:59Z
dc.date.issued2016-12-08
dc.description.abstractAtherosclerosis is a major cause of morbidity and mortality in western world. Bone morphogenetic proteins are secreted regulatory proteins that regulate various processes throughout human body. Recent studies indicate their presence in atherosclerotic plaques and emerging role in plaque development. Since monocytes are the key effector cells in atherosclerosis, the aim of this thesis was to investigate the actions of BMP-2 and -7 on monocyte thrombogenicity and motility. In our first paper we investigated the effects of BMP-2 on TF expression in human mononuclear cells (MNCs). We showed that BMP-2 induced phosphorylation of Smad 1/5/8, thus activating the canonical BMP signaling pathway. Though BMP-2 had no effect on the baseline TF expression, it was able to significantly reduce LPS-induced TF expression. When MNCs were pretreated with BMP-2 prior to LPS stimulation, a marked decrease in phosphorylation of ERK1/2, JNK and p38 was observed. BMP-2 also blocked the activation of AP-1 transcription factor, as was shown by use of AP-1 or NFkB sensitive luciferase constructs. This study shows that BMP-2 reduces LPS-induced TF expression in human MNCs by reducing activation of ERK1/2, JNK and p38 as well as blockade of AP-1 transcription factor. In our second and third papers we investigated the signaling pathways behind the ability of BMP-7 to induce TF in human MNCs. We showed that BMP-7 upregulates both TF protein levels, surface presentation and procoagulant activity as well as mRNA levels. BMP-7 was able to induce phosphorylation of ERK1/2, JNK and p38, signaling kinases essential in regulation of TF gene expression. Using luciferase constructs driven by either wildtype or mutated F3 gene promoters we showed that intact NFkB binding site on the F3 promoter is necessary for BMP-7-induced TF expression. Experiments with NFkB inhibitor, JSH-23, supported this finding. In our forth paper we present a novel function for BMP-7 – regulation of monocyte motility. Human monocytes pretreated with BMP-7 crawl for longer distances, attach to endothelium more readily and migrate faster through endothelial monolayers and show higher levels of active beta2 integrins on the cell surface. The observed effects were dependent on the activation of Akt/FAK signaling pathway and can be blocked by either natural BMP antagonist Noggin or synthetic BMP type 1 receptor inhibitor, Dorsomorphin.en_US
dc.description.doctoraltypeph.d.en_US
dc.description.popularabstractAterosklerose er en lokalisert fortykkelse i åreveggen. Det aterosklerotiske plakket kan sprekke og gi opphav til dannelse av en blodpropp (trombose) som kan okkludere sirkulasjon og hindre blodforsyning til målorganet (f.eks. hjerteinfarkt). Aterotrombose er den viktigste årsaken til sykelighet og død i vestlige land. De hvite blodcellene, og da spesielt monocyttene, spiller en viktig rolle i utviklingen av aterosklerose og påfølgende dannelse av blodpropp. Nyere studier har vist at benmorfogene proteiner (BMPs) kan kobles til utvikling av aterosklerose og dens komplikasjoner. I dette arbeidet har vi studerte mekanismene for BMPs virkning på monocytter. Vi har vist at noen av BMP'er har motsatte virkning på aktivering av vevsfaktor (aktivator av blodlevring) i monocytter. BMP2 blokkerer vevsfaktor, mens BMP7 induserer den. Vi har også studert en helt ny funksjon for BMP7, nemlig dets evne til å påvirke monocytters evne til å bevege seg. Vi har vist at BMP7 kan øke tilstrømningen av monocytter inn i aterosklerotiske plakk, og dermed øke risikoen for komplikasjoner, hyppigst - blodproppdannelse. Vi utforsker nå også mulighetene for å hindre disse effektene. Kunnskap om de molekylære mekanismene for disse funnene vil bedre vår forståelse av utviklingen av aterosklerose og kan hjelpe oss til å utvikle nye behandlingsmetoder i fremtiden.en_US
dc.description.sponsorshipNorwegian Research Council K.G. Jebsen Thrombosis Research and Expertise Center (TREC)en_US
dc.descriptionThe papers of this thesis are not available in Munin. <br> Paper I: Egorina, E. M., Sovershaev, T. A., Hansen, J. B., Sovershaev, M. A.: “BMP-2 inhibits TF expression in human monocytes by shutting down MAPK signaling and AP-1 transcriptional activity”. Available in <a href=http://dx.doi.org/10.1016/j.thromres.2011.10.024> Thromb Res. 2012, 129(4):e106-11. </a> <br> Paper II: Sovershaev, M. A., Egorina, E. M., Sovershaev, T. A., Svensson, B., Hansen, J. B.: “Increased expression of TF in BMP-7-treated human mononuclear cells depends on activation of select MAPK signaling pathways”. Available in <a href=http://dx.doi.org/10.1016/j.thromres.2011.07.027> Thromb Res. 2011, 128(6):e154-9. </a> <br> Paper III: Sovershaev, T. A., Egorina, E. M., Unruh, D., Bogdanov, V. Y., Hansen, J. B., Sovershaev, M. A. «BMP-7 induces TF expression in human monocytes by increasing F3 transcriptional activity”. Available in <a href=http://dx.doi.org/10.1016/j.thromres.2014.11.031> Thromb Res. 2015, 135(2):398-403. </a> <br> Paper IV: Sovershaev, T. A., Unruh, D., Sveinbjørnsson, D., Fallon, J. T., Hansen, J. B., Bogdanov, V. Y., Sovershaev, M. A.: “A novel role of bone morphogenetic protein-7 in the regulation of adhesion and migration of human monocytic cells”. (Manuscript). Published version available in <a href=http://dx.doi.org/10.1016/j.thromres.2016.09.018> Thromb Res. 2016, 147:24–31. </a>en_US
dc.identifier.urihttps://hdl.handle.net/10037/10052
dc.language.isoengen_US
dc.publisherUiT The Arctic University of Norwayen_US
dc.publisherUiT Norges arktiske universiteten_US
dc.rights.accessRightsopenAccessen_US
dc.subject.courseIDDOKTOR-003
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical molecular biology: 711en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk molekylærbiologi: 711en_US
dc.titleBone morphogenetic proteins: Novel mediators of atherothrombosisen_US
dc.typeDoctoral thesisen_US
dc.typeDoktorgradsavhandlingen_US


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