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) |