Nitro-fatty acid modulates expression of CD36 and LRP1 scavenger receptors on RAW264.7 macrophages.

VAZQUEZ M; GUTIERREZ MV; ACTIS-DATO V; CHIABRANDO G; BONACCI G

Baltimore

Congreso; 24th Annual Meeting of the Society for Redox Biology & Medicine; 2017

Society for Redox Biology & Medicine

Macrophage plays a pivotal role in early stages of atherosclerosis. Inflammatory profile and uncontrolled modified-lipoprotein uptake through scavenger receptors (SR) such as CD36, LRP1 and SRA-1 in macrophages drive to pathological conditions. Our group has reported in patients that decreased expression of LRP1 in circulating monocytes is associated with a pro-inflammatory profile and subclinical atherosclerosis. In addition, the activation of macrophages induces the formation of numerous bioactive lipids mediators, such as nitro-fatty acid (NO2-FA), which exhibit important anti-inflammatory and cytoprotective actions. In this study we investigated the role of NO2-FAs on SRs expression and macrophage foam cell formation. Both CD36 and LRP1 showed upregulation in a NO2-FA dose dependent manner by western blot and flow cytometry. Enhanced CD36 expression was in direct relation with an increased uptake of oxLDL as demonstrated by Oil Red O stain. NO2-FA regulation of CD36 seems to be mediated by Keap1-Nrf2-dependent pathway and independent of PPAR-γ, as was evaluated using pharmacological inhibitors and knockdown (siRNA) strategies. Unlike CD36, no transcriptional changes were observed on LRP1 mRNA levels. Besides that NO2-FA induction of LRP1 protein expression was independent of protein synthesis by using cycloheximide. Thus, LRP1 regulation might be caused by altered proteasomal degradation or cellular trafficking. Therefore, NO2-FA regulates the expression at different cellular level of two important SR with dissimilar implications in cardiovascular disease. On one side, the athero-protective LRP1 and on the other side the proatherogenic receptor CD36. Thus, the beneficial action ascribed to NO2-FAs in in vivo models of atherosclerosis may be the result of a complex balance between anti-inflammatory, pro- and anti-atherogenic pathways in macrophage.