Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages
Articolo
Data di Pubblicazione:
2017
Citazione:
Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages / M.P. Adorni, E. Cipollari, E. Favari, I. Zanotti, F. Zimetti, A. Corsini, C. Ricci, F. Bernini, N. Ferri. - In: ATHEROSCLEROSIS. - ISSN 0021-9150. - 256(2017), pp. 1-6. [10.1016/j.atherosclerosis.2016.11.019]
Abstract:
Background and aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) may have extra-hepatic effects on cholesterol homeostasis of vascular macrophages. In this study, we aimed to investigate PCSK9 role on the anti-atherogenic process of ATP binding cassette transporter A1 (Abca1)-mediated cholesterol efflux. Methods Abca1-mediated cholesterol efflux was evaluated by a radioisotopic technique in mouse peritoneal macrophages (MPM) from wild-type (WT) or LDL receptor knock-out (Ldlr−/−) mice exposed to human recombinant PCSK9, in the presence of liver X receptor/retinoid X receptor (LXR/RXR) ligands or acetylated LDL (AcLDL) to stimulate Abca1 expression. Protein and gene expression was evaluated by Western blot and quantitative real time PCR, respectively. Results PCSK9 inhibited Abca1-mediated cholesterol efflux induced by LXR/RXR agonists in WT MPM (−55%, p < 0.05) but not in Ldlr−/− MPM. This effect was fully abrogated by the co-incubation with an anti-PCSK9 antibody. The inhibition of Abca1-dependent efflux induced by PCSK9 was associated with a reduction of Abca1 protein expression only in WT cells. Abca1 gene expression was significantly downregulated by PCSK9 in WT macrophages (−64%, p < 0.001) and, to a lesser extent, in MPM lacking Ldlr (−35%, p < 0.001). The inhibitory effect on Abca1-mediated efflux was also confirmed in AcLDL-treated macrophages. PCSK9 had a marginal or no effect on the expression of the lipid transporters Sr-b1 and Abcg1. Conclusions PCSK9 plays a direct role on Abca1-mediated cholesterol efflux through a downregulation of Abca1 gene and Abca1 protein expression. This extrahepatic effect may influence relevant steps in the pathogenesis of atherosclerosis, such as foam cell formation.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
ABCA1; Cholesterol efflux; Macrophage; PCSK9; Cardiology and Cardiovascular Medicine
Elenco autori:
M.P. Adorni, E. Cipollari, E. Favari, I. Zanotti, F. Zimetti, A. Corsini, C. Ricci, F. Bernini, N. Ferri
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