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NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
Örebro universitet, Institutionen för medicinska vetenskaper.ORCID-id: 0000-0002-4589-6440
Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Vise andre og tillknytning
2016 (engelsk)Inngår i: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, nr 5, artikkel-id e003031Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background: The NLR family, pyrin domain containing 3 (NLRP3) inflammasome is an interleukin (IL)-1β and IL-18 cytokine processing complex that is activated in inflammatory conditions. The role of the NLRP3 inflammasome in the pathogenesis of atherosclerosis and myocardial infarction is not fully understood.

Methods and Results: Atherosclerotic plaques were analyzed for transcripts of the NLRP3 inflammasome, and for IL-1β release. The Swedish First-ever myocardial Infarction study in Ac-county (FIA) cohort consisting of DNA from 555 myocardial infarction patients and 1016 healthy individuals was used to determine the frequency of 4 single nucleotide polymorphisms (SNPs) from the downstream regulatory region of NLRP3. Expression of NLRP3, Apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1 (CASP1), IL1B, and IL18 mRNA was significantly increased in atherosclerotic plaques compared to normal arteries. The expression of NLRP3 mRNA was significantly higher in plaques of symptomatic patients when compared to asymptomatic ones. CD68-positive macrophages were observed in the same areas of atherosclerotic lesions as NLRP3 and ASC expression. Occasionally, expression of NLRP3 and ASC was also present in smooth muscle cells. Cholesterol crystals and ATP induced IL-1β release from lipopolysaccharide-primed human atherosclerotic lesion plaques. The minor alleles of the variants rs4266924, rs6672995, and rs10733113 were associated with NLRP3 mRNA levels in peripheral blood mononuclear cells but not with the risk of myocardial infarction.

Conclusions: Our results indicate a possible role of the NLRP3 inflammasome and its genetic variants in the pathogenesis of atherosclerosis.

sted, utgiver, år, opplag, sider
Hoboken, USA: Wiley-Blackwell Publishing Inc., 2016. Vol. 5, nr 5, artikkel-id e003031
Emneord [en]
Inflammasome, interleukin-1b, myocardial infarction, NLRP3, polymorphism
HSV kategori
Forskningsprogram
Kardiologi
Identifikatorer
URN: urn:nbn:se:oru:diva-50441DOI: 10.1161/JAHA.115.003031ISI: 000386711200020PubMedID: 27207962OAI: oai:DiVA.org:oru-50441DiVA, id: diva2:931116
Forskningsfinansiär
Swedish Research Council, 6816 K2012-64X-12233-13-3Swedish Heart Lung Foundation, 20110359Magnus Bergvall Foundation
Merknad

Funding Agencies:

Center of Excellence for Research on Inflammation and Cardiovascular Disease (CERIC) Linnaeus Center8703

Foundation for Strategic Research, Uppdrag Besegra Stroke P581/2011-123

Strategic Cardiovascular Programs of Karolinska Institutet, Stockholm County Council ALF 20110279

Örebro University

Sigurd and Elsa Goljes Foundation

Tilgjengelig fra: 2016-05-26 Laget: 2016-05-26 Sist oppdatert: 2018-09-12bibliografisk kontrollert
Inngår i avhandling
1. Innate immunity in human atherosclerosis and myocardial infarction: Role of CARD8 and NLRP3
Åpne denne publikasjonen i ny fane eller vindu >>Innate immunity in human atherosclerosis and myocardial infarction: Role of CARD8 and NLRP3
2017 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Atherosclerosis is complex inflammatory disease of the arterial wall with progressive accumulation of lipids and narrowing of the vessel. Increasing evidence suggest that inflammation plays an important role in plaque stability and often accelerate cardiovascular events such as myocardial infarction (MI). Among the vast number of inflammatory cytokines, IL-1β is known to be a key modulator in vessel wall inflammation and acceleration of the atherosclerotic process. The biologically active IL-1β is regulated by a multiprotein complex known as the NLRP3 inflammasome complex. In this thesis, we have focused on polymorphisms in the NLRP3 and CARD8 genes and their possible association to atherosclerosis and/or MI. We have also investigated the expression of inflammasome components NLRP3 and CARD8 in atherosclerosis and the role of genetic variants for the expression of these genes. The expression of NLRP3, CARD8, ASC, caspase-1, IL-1β, and IL-18 were found significantly upregulated in atherosclerotic lesions compared to normal arteries. Human carotid plaques not only express the NLRP3 inflammasome, but also release IL-1β upon exposure to lipopolysaccharide (LPS), adenosine triphosphate (ATP) and cholesterol crystals, which suggest NLRP3 inflammasome activation in human atherosclerotic lesions. Also, CARD8 was found to be important in the regulation of several inflammatory markers in endothelial cells, like RANTES, IP10 and ICAM-1. We further assessed the potential association of a CARD8 polymorphism and polymorphisms located downstream of the NLRP3 gene to the risk of MI in two independent Swedish cohorts. The CARD8 variant exhibited no association to risk of MI in either of the two cohorts. Some of the minor alleles of NLRP3 variants were associated with increased IL-1β levels and to NLRP3 mRNA levels in peripheral blood monocytic cells (PBMC). Taken together, the present thesis shows that NLRP3 inflammasome activation and increased expression of CARD8 in the atherosclerotic plaque might be possible contributors to the enhanced inflammatory response and leukocyte infiltration in the pathophysiology of atherosclerosis.

sted, utgiver, år, opplag, sider
Örebro: Örebro University, 2017. s. 77
Serie
Örebro Studies in Medicine, ISSN 1652-4063 ; 154
Emneord
Atherosclerosis, Inflammasome, NLRP3, CARD8, Myocardial infarction, Endothelial cells, Polymorphism, IL-1β, Cytokines, Innate immunity
HSV kategori
Forskningsprogram
Biomedicin
Identifikatorer
urn:nbn:se:oru:diva-53482 (URN)978-91-7529-173-4 (ISBN)
Disputas
2017-01-27, Campus USÖ, hörsal C1, Södra Grev Rosengatan 30, Örebro, 09:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2016-11-14 Laget: 2016-11-14 Sist oppdatert: 2018-01-13bibliografisk kontrollert

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