PMID- 24389343 OWN - NLM STAT- MEDLINE DCOM- 20141022 LR - 20140128 IS - 1095-8584 (Electronic) IS - 0022-2828 (Linking) VI - 67 DP - 2014 Feb TI - Systemic toll-like receptor and interleukin-18 pathway activation in patients with acute ST elevation myocardial infarction. PG - 94-102 LID - S0022-2828(13)00370-2 [pii] LID - 10.1016/j.yjmcc.2013.12.021 [doi] AB - 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-1alpha. 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. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - van der Pouw Kraan, Tineke C T M AU - van der Pouw Kraan TC AD - Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: t.vanderpouwkraan@vumc.nl. FAU - Bernink, Flip J P AU - Bernink FJ AD - Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands. FAU - Yildirim, Cansu AU - Yildirim C AD - Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands. FAU - Koolwijk, Pieter AU - Koolwijk P AD - Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands. FAU - Baggen, Josefien M AU - Baggen JM AD - Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands. FAU - Timmers, Leo AU - Timmers L AD - Department of Cardiology, University Medical Center Utrecht, The Netherlands. FAU - Beek, Aernout M AU - Beek AM AD - Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands. FAU - Diamant, Michaela AU - Diamant M AD - Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands. FAU - Chen, Weena J Y AU - Chen WJ AD - Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands. FAU - van Rossum, Albert C AU - van Rossum AC AD - Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands. FAU - van Royen, Niels AU - van Royen N AD - Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands. FAU - Horrevoets, Anton J G AU - Horrevoets AJ AD - Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands. FAU - Appelman, Yolande E AU - Appelman YE AD - Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands. LA - eng PT - Journal Article DEP - 20140103 PL - England TA - J Mol Cell Cardiol JT - Journal of molecular and cellular cardiology JID - 0262322 RN - 0 (Interleukin-18) RN - 0 (Toll-Like Receptor 4) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Gene Expression Profiling MH - Gene Expression Regulation MH - Humans MH - Interleukin-18/blood/genetics/*metabolism MH - Leukocytes/metabolism MH - Middle Aged MH - Myocardial Infarction/*physiopathology MH - Toll-Like Receptor 4/blood/genetics/*metabolism MH - Up-Regulation OTO - NOTNLM OT - AAR OT - Area at risk OT - CK-MB OT - EDV OT - End diastolic volume OT - HIF1 OT - HIF1A OT - Hypoxia induced factor 1 OT - IL-18 binding protein OT - IL-18BP OT - IL-18R OT - IL-R OT - Immune response OT - Interleukin receptor OT - LVEF OT - Left ventricular ejection fraction OT - MMP OT - Matrix metalloproteinase OT - Myocardial infarction OT - NFKBIA OT - Nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor alpha OT - PCR OT - Phosphocreatine kinase isoenzymes CKM and CKB OT - Polymerase chain reaction OT - STEMI OT - TLR OT - TNF OT - Toll-like receptor OT - Toll-like receptors OT - Tumor necrosis factor alpha EDAT- 2014/01/07 06:00 MHDA- 2014/10/23 06:00 CRDT- 2014/01/07 06:00 PHST- 2013/09/09 00:00 [received] PHST- 2013/12/09 00:00 [revised] PHST- 2013/12/25 00:00 [accepted] PHST- 2014/01/07 06:00 [entrez] PHST- 2014/01/07 06:00 [pubmed] PHST- 2014/10/23 06:00 [medline] AID - S0022-2828(13)00370-2 [pii] AID - 10.1016/j.yjmcc.2013.12.021 [doi] PST - ppublish SO - J Mol Cell Cardiol. 2014 Feb;67:94-102. doi: 10.1016/j.yjmcc.2013.12.021. Epub 2014 Jan 3.