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Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis

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dc.contributor Háskóli Íslands (HÍ)
dc.contributor University of Iceland (UI)
dc.contributor.author Aldi, Silvia
dc.contributor.author Matic, Ljubica Perisic
dc.contributor.author Hamm, Gregory
dc.contributor.author van Keulen, Daniëlle
dc.contributor.author Tempel, Dennie
dc.contributor.author Holmstrøm, Kim
dc.contributor.author Szwajda, Agnieszka
dc.contributor.author Nielsen, Boye Schnack
dc.contributor.author Emilsson, Valur
dc.contributor.author Ait-Belkacem, Rima
dc.contributor.author Lengquist, Mariette
dc.contributor.author Paulsson-Berne, Gabrielle
dc.contributor.author Eriksson, Per
dc.contributor.author Lindeman, Jan H.N.
dc.contributor.author Gool, Alain J.
dc.contributor.author Stauber, Jonathan
dc.contributor.author Hedin, Ulf
dc.contributor.author Hurt-Camejo, Eva
dc.date.accessioned 2020-01-10T15:38:34Z
dc.date.available 2020-01-10T15:38:34Z
dc.date.issued 2018-09-21
dc.identifier.citation Aldi, S., Matic, L., Hamm, G., Van Keulen, D., Tempel, D., Holmstrøm, K., . . . Hurt-Camejo, E. (2018). Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis. Molecular Therapy - Methods & Clinical Development, 10, 17-28.
dc.identifier.issn 2329-0501
dc.identifier.uri https://hdl.handle.net/20.500.11815/1450
dc.description Publisher's version (útgefin grein).
dc.description.abstract Variants in thePLPP3gene encoding for lipid phosphatephosphohydrolase 3 have been associated with susceptibilityto atherosclerosis independently of classical risk factors.PLPP3 inactivates lysophosphatidic acid (LPA), a pro-inflam-matory, pro-thrombotic product of phospholipase activity.Here we performed thefirst exploratory analysis of PLPP3,LPA, and LPA receptors (LPARs 1–6) in human atheroscle-rosis. PLPP3 transcript and protein were repressed whencomparing plaques versus normal arteries and plaques fromsymptomatic versus asymptomatic patients, and they werenegatively associated with risk of adverse cardiovascularevents. PLPP3 localized to macrophages, smooth muscle,and endothelial cells (ECs) in plaques. LPAR 2, 5, and espe-cially 6 showed increased expression in plaques, with LPAR6localized in ECs and positively correlated to PLPP3. Utilizingin situmass spectrometry imaging, LPA and its precursorswere found in the plaquefibrous cap, co-localizing withPLPP3 and LPAR6.In vitro, PLPP3 silencing in ECs underLPA stimulation resulted in increased expression of adhesionmolecules and cytokines. LPAR6 silencing inhibited LPA-induced cell activation, but not when PLPP3 was silencedsimultaneously. Our results show that repression of PLPP3plays a key role in atherosclerosis by promoting EC activation.Altogether, the PLPP3 pathway represents a suitable target forinvestigations into novel therapeutic approaches to ameliorateatherosclerosis.
dc.description.sponsorship We thank Germán Camejo for carefully reading the manuscript andvaluable comments. The research leading to these results has receivedmajor funding from the European Union Seventh Framework Pro-gramme (FP7/2007-2013) under grant agreement 602936 (CarTarDisproject). This work was conducted with support from the SwedishHeart and Lung Foundation, the Swedish Research Council(K2009-65X-2233-01-3, K2013-65X-06816-30-4, and 349-2007-8703), Uppdrag Besegra Stroke (P581/2011-123), the Strategic Car-diovascular Programs of Karolinska Institutet and Stockholm CountyCouncil, the Stockholm County Council (ALF2011-0260 and ALF-2011-0279), the Foundation for Strategic Research, and the EuropeanCommission (CarTarDis, AtheroRemo, VIA, and AtheroFlux pro-jects). L.P.M. is the recipient of fellowships from the Swedish Societyfor Medical Research (SSMF) and the Heart and Lung Foundation(HLF, Sweden), and L.P.M. acknowledges research grants fromTore Nilsson, Magnus Bergvall, and Karolinska Institutet Founda-tions of Sweden.
dc.format.extent 17-28
dc.language.iso en
dc.publisher Elsevier BV
dc.relation Verður að byrja á "info:eu-repo/grantAgreement/EC/FP7/602936
dc.relation.ispartofseries Molecular Therapy - Methods & Clinical Development;10
dc.rights info:eu-repo/semantics/openAccess
dc.subject Atherosclerosis
dc.subject Therapy
dc.subject Biobank profiling
dc.subject Hjartasjúkdómar
dc.subject Lyfjagerð
dc.subject Lyfjafræði
dc.title Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis
dc.type info:eu-repo/semantics/article
dcterms.license This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
dc.description.version Peer Reviewed
dc.identifier.journal Molecular Therapy - Methods & Clinical Development
dc.identifier.doi 10.1016/j.omtm.2018.05.003
dc.contributor.department Faculty of Pharmaceutical Sciences (UI)
dc.contributor.department Lyfjafræðideild (HÍ)
dc.contributor.school Heilbrigðisvísindasvið (HÍ)
dc.contributor.school School of Health Sciences (UI)

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