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Innate immunity in human atherosclerosis and myocardial infarction: Role of CARD8 and NLRP3
Örebro University, School of Medical Sciences.ORCID iD: 0000-0002-4589-6440
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
Keyword [en]
Atherosclerosis, Inflammasome, NLRP3, CARD8, Myocardial infarction, Endothelial cells, Polymorphism, IL-1β, Cytokines, Innate immunity
National Category
Other Basic Medicine
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-53482ISBN: 978-91-7529-173-4 (print)OAI: oai:DiVA.org:oru-53482DiVA, id: diva2:1046323
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
List of papers
1. NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
Open this publication in new window or tab >>NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
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2016 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, no 5, article id e003031Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Hoboken, USA: Wiley-Blackwell Publishing Inc., 2016
Keyword
Inflammasome, interleukin-1b, myocardial infarction, NLRP3, polymorphism
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:oru:diva-50441 (URN)10.1161/JAHA.115.003031 (DOI)000386711200020 ()27207962 (PubMedID)
Funder
Swedish Research Council, 6816 K2012-64X-12233-13-3Swedish Heart Lung Foundation, 20110359Magnus Bergvall Foundation
Note

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

Available from: 2016-05-26 Created: 2016-05-26 Last updated: 2018-04-27Bibliographically approved
2. Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals
Open this publication in new window or tab >>Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals
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2013 (English)In: Biomedical Reports, ISSN 2049-9434, Vol. 1, no 6, p. 879-882Article in journal (Refereed) Published
Abstract [en]

Inflammation is a multifaceted process that underlies the pathophysiology of acute myocardial infarction (MI). Variations in the inflammasome‑related NLRP3 gene have been associated with risk for a number of different inflammatory diseases. Therefore, Q705K polymorphism in NLRP3 gene likely confers susceptibility to risk for MI. A First‑ever myocardial Infarction study in Ac‑county (FIA) cohort comprising 555 MI patients and 1,016 controls was used to genotype rs35829419 in the NLRP3 gene by TaqMan single‑nucleotide polymorphism assay. C‑reactive protein (CRP) was measured in the study participants by ELISA. The results showed no significant association between the variant rs35829419 and MI. However, the minor A allele of the rs35829419 polymorphism conferred a protective effect against the risk of developing MI in females. The minor A allele of rs35829419 polymorphism was also associated with increased CRP levels in males. Results of the study suggested a gender‑specific deregulation of NLRP3 gene mediated by rs35829419 polymorphism that confers protection against MI in females but has no effect on MI susceptibility in males. However, the rs35829419 polymorphism was associated with increased CRP levels among the male subjects, thereby demonstrating the possible effect of the Q705K polymorphism in elevating the basal active state of innate immune response.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:oru:diva-35448 (URN)10.3892/br.2013.155 (DOI)
Available from: 2014-06-19 Created: 2014-06-19 Last updated: 2017-10-18Bibliographically approved
3. CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation
Open this publication in new window or tab >>CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation
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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
Keyword
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:nbn:se:oru:diva-30985 (URN)10.1042/CS20120572 (DOI)000323852600009 ()23611467 (PubMedID)2-s2.0-84880141884 (Scopus ID)
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: 2017-12-06Bibliographically approved
4. CARD8, a protein of innate immunity regulates the release of inflammatory cytokines in human endothelial cells
Open this publication in new window or tab >>CARD8, a protein of innate immunity regulates the release of inflammatory cytokines in human endothelial cells
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(English)Manuscript (preprint) (Other academic)
National Category
Other Basic Medicine
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-54142 (URN)
Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2018-01-13Bibliographically approved

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Paramel Varghese, Geena

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