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CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.ORCID iD: 0000-0002-4589-6440
Atherosclerosis Research Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Atherosclerosis Research Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
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2013 (English)In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 125, no 8, p. 401-407Article in journal (Refereed) Published
Abstract [en]

Inflammation is a key factor in the development of atherosclerotic coronary artery disease. It is promoted through the inflammasome, a molecular machine that produces IL (interleukin)-1 beta in response to cholesterol crystal accumulation in macrophages. The CARD8 (caspase recruitment domain 8) protein modulates this process by suppressing caspase 1 and the transcription factor NF-kappa B (nuclear factor kappa B). The expression of CARD8 mRNA was examined in atherosclerotic vascular tissue and the impact on MI (myocardial infarction) of a polymorphism in the CARD8 gene determined. CARD8 mRNA was analysed by microarray of human atherosclerotic tissue and compared with transplant donor arterial tissue. Microarray analysis was performed for proximal genes associated with the rs2043211 locus in plaque. The CARD8 rs2043211 polymorphism was analysed by genotyping of two Swedish MI cohorts, FIA (First Myocardial Infarction in Northern Sweden) and SCARF (Stockholm Coronary Atherosclerosis Risk Factor). The CRP (C-reactive protein) level was measured in both cohorts, but the levels of the pro-inflammatory cytokines IL-1 beta, IL-18, TNF (tumour necrosis factor) and MCP-1 (monocyte chemoattractant protein) were measured in sera available from the SCARF cohort. CARD8 mRNA was highly expressed in atherosclerotic plaques compared with the expression in transplant donor vessel (P < 0.00001). The minor allele was associated with lower expression of CARD8 in the plaques, suggesting that CARD8 may promote inflammation. Carriers of the minor allele of the rs2043211 polymorphism also displayed lower circulating CRP and lower levels of the pro-atherosclerotic chemokine MCP-1. However, no significant association could be detected between this polymorphism and MI in the two cohorts. Genetic alterations in the CARD8 gene therefore seem to be of limited importance for the development of MI.

Place, publisher, year, edition, pages
London, United Kingdom: Portland Press, 2013. Vol. 125, no 8, p. 401-407
Keywords [en]
Caspase activation and recruitment domain 8 (CARD8), cytokines, gene polymorphism, inflammasome, myocardial infarction, rs2043211
National Category
Medical and Health Sciences Genetics
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-30985DOI: 10.1042/CS20120572ISI: 000323852600009PubMedID: 23611467Scopus ID: 2-s2.0-84880141884OAI: oai:DiVA.org:oru-30985DiVA, id: diva2:651851
Funder
Swedish Heart Lung FoundationSwedish Research Council, 521-2009-4203 349-2007-8703
Note

Funding Agencies:

Magnus Bergvalls Foundation

Örebro University

Available from: 2013-09-27 Created: 2013-09-27 Last updated: 2018-08-27Bibliographically approved
In thesis
1. Innate immunity in human atherosclerosis and myocardial infarction: Role of CARD8 and NLRP3
Open this publication in new window or tab >>Innate immunity in human atherosclerosis and myocardial infarction: Role of CARD8 and NLRP3
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Örebro: Örebro University, 2017. p. 77
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 154
Keywords
Atherosclerosis, Inflammasome, NLRP3, CARD8, Myocardial infarction, Endothelial cells, Polymorphism, IL-1β, Cytokines, Innate immunity
National Category
Other Basic Medicine
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-53482 (URN)978-91-7529-173-4 (ISBN)
Public defence
2017-01-27, Campus USÖ, hörsal C1, Södra Grev Rosengatan 30, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-11-14 Created: 2016-11-14 Last updated: 2018-01-13Bibliographically approved

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Paramel, GeenaElmabsout, AliSärndahl, EvaSirsjö, AllanFransén, Karin

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