L5-LDL from ST-elevation myocardial infarction patients induces IL-1ß production via LOX-1 and NLRP3 inflammasome activation in macrophages.
Am J Physiol Heart Circ Physiol
; 312(2): H265-H274, 2017 Feb 01.
Article
en En
| MEDLINE
| ID: mdl-27864235
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)-1ß, in the pathogenesis of STEMI. Clinical data showed that plasma levels of L5-LDL and IL-1ß 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-1ß 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-1ß. 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-1ß in macrophages. Furthermore, blockade LOX-1 with neutralizing antibody also inhibited L5-LDL-induced IL-1ß in human peripheral blood mononuclear cell-derived macrophages. In conclusion, L5-LDL induces IL-1ß 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-1ß 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-1ß in ST-segment elevation myocardial infarction (STEMI). We elucidate the molecular mechanism underlying L5-LDL-induced production of IL-1ß 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-1ß.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores Depuradores de Clase E
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Interleucina-1beta
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Infarto del Miocardio con Elevación del ST
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Proteína con Dominio Pirina 3 de la Familia NLR
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Lipoproteínas LDL
/
Macrófagos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Am J Physiol Heart Circ Physiol
Asunto de la revista:
CARDIOLOGIA
/
FISIOLOGIA
Año:
2017
Tipo del documento:
Article