title: Systemic toll-like receptor and interleukin-18 pathway activation in patients with acute ST elevation myocardial infarction.
abstract: Acute myocardial infarction (AMI) is accompanied by increased expression of Toll like receptors (TLR)-2 and TLR4 on circulating monocytes. In animal models, blocking TLR2/4 signaling reduces inflammatory cell influx and infarct size. The clinical consequences of TLR activation during AMI in humans are unknown, including its role in long-term cardiac functional outcome Therefore, we analyzed gene expression in whole blood samples from 28 patients with an acute ST elevation myocardial infarction (STEMI), enrolled in the EXenatide trial for AMI patients (EXAMI), both at admission and after 4-month follow-up, by whole genome expression profiling and real-time PCR. Cardiac function was determined by cardiac magnetic resonance (CMR) imaging at baseline and after 4-month follow-up. TLR pathway activation was shown by increased expression of TLR4 and its downstream genes, including IL-18R1, IL-18R2, IL-8, MMP9, HIF1A, and NFKBIA. In contrast, expression of the classical TLR-induced genes, TNF, was reduced. Bioinformatics analysis and in vitro experiments explained this noncanonical TLR response by identification of a pivotal role for HIF-1α. The extent of TLR activation and IL-18R1/2 expression in circulating cells preceded massive troponin-T release and correlated with the CMR-measured ischemic area (R=0.48, p=0.01). In conclusion, we identified a novel HIF-1-dependent noncanonical TLR activation pathway in circulating leukocytes leading to enhanced IL-18R expression which correlated with the magnitude of the ischemic area. This knowledge may contribute to our mechanistic understanding of the involvement of the innate immune system during STEMI and may yield diagnostic and prognostic value for patients with myocardial infarction.
authors.affiliation: Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: t.vanderpouwkraan@vumc.nl.
authors.forename: Tineke C T M
authors.initials: TC
authors.lastname: van der Pouw Kraan
authors.affiliation: Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Flip J P
authors.initials: FJ
authors.lastname: Bernink
authors.affiliation: Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Cansu
authors.initials: C
authors.lastname: Yildirim
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Koolwijk
authors.affiliation: Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Josefien M
authors.initials: JM
authors.lastname: Baggen
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, The Netherlands.
authors.forename: Leo
authors.initials: L
authors.lastname: Timmers
authors.affiliation: Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Aernout M
authors.initials: AM
authors.lastname: Beek
authors.affiliation: Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.affiliation: Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Weena J Y
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Albert C
authors.initials: AC
authors.lastname: van Rossum
authors.affiliation: Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: van Royen
authors.affiliation: Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Anton J G
authors.initials: AJ
authors.lastname: Horrevoets
authors.affiliation: Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Yolande E
authors.initials: YE
authors.lastname: Appelman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D020382:Interleukin-18 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008875:Middle Aged; D009203:Myocardial Infarction / Q000503:physiopathology*; D051197:Toll-Like Receptor 4 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D020382:Interleukin-18; D051197:Toll-Like Receptor 4
keywords: AAR; Area at risk; CK-MB; EDV; End diastolic volume; HIF1; HIF1A; Hypoxia induced factor 1; IL-18 binding protein; IL-18BP; IL-18R; IL-R; Immune response; Interleukin receptor; LVEF; Left ventricular ejection fraction; MMP; Matrix metalloproteinase; Myocardial infarction; NFKBIA; Nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor alpha; PCR; Phosphocreatine kinase isoenzymes CKM and CKB; Polymerase chain reaction; STEMI; TLR; TNF; Toll-like receptor; Toll-like receptors; Tumor necrosis factor alpha