CONICET | Buscador de Institutos y Recursos Humanos

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 that patients with decreased expression of LRP1 in circulating monocytes are 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 (NO 2 -FA), which exhibit important anti-inflammatory and cytoprotective actions. In this study we investigated the role of NO 2 -FAs on SRs expression and macrophage foam cell formation. Both CD36 and LRP1 expression was upregulated at plasma membrane in a dose dependent manner. In RAW264.7 macrophages, NO 2 -FA enhanced CD36 expression in direct relation with an increased uptake of oxLDL that was inhibited by cycloheximide. NO 2 -FA regulations of CD36 suggest 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 but expression of LRP1 at plasma membrane was increased independently of protein synthesis (cycloheximide). Thus, LRP1 regulation could be caused by altered proteasomal degradation or cellular trafficking. Therefore, NO 2 -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 NO 2 -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.