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Am J Physiol Heart Circ Physiol. 2017 Feb 1;312(2):H265-H274. doi: 10.1152/ajpheart.00509.2016. Epub 2016 Nov 18.

L5-LDL from ST-elevation myocardial infarction patients induces IL-1β production via LOX-1 and NLRP3 inflammasome activation in macrophages.

Author information

1
Department of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan; and.
2
Cardiovasccular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
3
Department of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan; and lsc@ntu.edu.tw.

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.

NEW & NOTEWORTHY:

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.

KEYWORDS:

IL-1β; LOX-1; STEMI; acute myocardial infarction; electronegative LDL

PMID:
27864235
DOI:
10.1152/ajpheart.00509.2016
[Indexed for MEDLINE]
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