title: L5-LDL from ST-elevation myocardial infarction patients induces IL-1β production via LOX-1 and NLRP3 inflammasome activation in macrophages.
abstract: L5-LDL, the most electronegative LDL associated with major cardiovascular risks, significantly rises in patients with ST-segment elevation myocardial infarction (STEMI). The inflammatory nature of atherosclerotic vascular diseases has prompted us to investigate whether L5-LDL induces the production of inflammatory cytokines, especially vascular ischemia-related interleukin (IL)-1β, in the pathogenesis of STEMI. Clinical data showed that plasma levels of L5-LDL and IL-1β were higher in the STEMI patients than in the controls (P < 0.05). In THP-1-derived human macrophages, L5-LDL significantly increased the levels of both IL-1β and cleaved caspase-1, indicating the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasomes by L5-LDL. Knockdown of NLRP3 and its adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) resulted in decreased L5-LDL-induced IL-1β. Furthermore, knock down of the lectin-type oxidized LDL receptor (LOX-1) in THP-1 cells attenuated L5-LDL-induced activation of NF-κB and caspase-1, leading to subsequent inhibition of IL-1β in macrophages. Furthermore, blockade LOX-1 with neutralizing antibody also inhibited L5-LDL-induced IL-1β in human peripheral blood mononuclear cell-derived macrophages. In conclusion, L5-LDL induces IL-1β production in macrophages by activation of NF-κB and caspase-1 through the LOX-1-dependent pathway. This study represents the evidence linking L5-LDL and the inflammatory cytokine IL-1β in STEMI, and identifies L5-LDL as a novel therapeutic target in acute myocardial infarction.
  This study represents the evidence linking L5-LDL and the inflammatory cytokine IL-1β in ST-segment elevation myocardial infarction (STEMI). We elucidate the molecular mechanism underlying L5-LDL-induced production of IL-1β in macrophages. The results showed that L5-LDL induced activation of caspase-1 and NF-κB through the lectin-type oxidized LDL receptor (LOX-1)-dependent pathway, leading to the production of IL-1β.
authors.affiliation: Department of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan; and.
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Yang
authors.affiliation: Cardiovasccular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan; and lsc@ntu.edu.tw.
authors.forename: Shao-Chun
authors.initials: SC
authors.lastname: Lu
mesh_terms: D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000276:immunology; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics; D055785:Gene Knockdown Techniques; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics; D006801:Humans; D058847:Inflammasomes / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear; D008077:Lipoproteins, LDL / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000276:immunology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072657:ST Elevation Myocardial Infarction / Q000235:genetics / Q000276:immunology*; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; C508585:IL1B protein, human; C508600:IL6 protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C495137:OLR1 protein, human; C402202:PYCARD protein, human; D012333:RNA, Messenger; D051127:Scavenger Receptors, Class E; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C574964:low-density lipoprotein L5, human; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D020170:Caspase 1
keywords: IL-1β; LOX-1; STEMI; acute myocardial infarction; electronegative LDL