Aim
Cholesterol accumulation in arterial cells triggers atherogenesis at the cellular level. The aim of this work was to identify the genes responsible for cholesterol accumulation caused by modified LDL.
Methods
Monocytes were isolated from the blood of healthy individuals and futher differentiated into macrophages. Intracellular cholesterol accumulation was induced by incubation of cultured cells with native and modified LDL: oxidized, desialylated and acetylated. Total RNA was sequenced using Illumina HiSeq 3000. The role of identified by Genexplain platform genes in cholesterol accumulation were evaluated by siRNA.
Results
Modified LDL caused significant 1.5- to 3-fold increase in intracellular cholesterol level as compared with native LDL. Treatment of macrophages with modified LDL resulted in up-regulation of genes involved in the inflammation and immune responses, without affecting the activity of known cholesterol metabolism-regulating genes. Integrated promoter-pathway analysis was performed to identify the master-regulators not only associated but also responsible for cholesterol accumulation. We identified that PERK/eIF2α/CHOP signaling pathway inducing by ER-stress is highly responsible for intracellular cholesterol accumulation. Moreover, the knockdown of gene PERK in human macrophages totally canceled the cholesterol accumulation under the treatment by modified LDL.
Conclusions
We assume that ER-stress-induced inflammation could play the critical role in foam cell formation.
This work was supported by Russian Foundation of Basic Research (Grant No. 18-34-00997).

05 - MODIFIED LDLS ACTIVATE ER-STRESS-INDUCED INFLAMMATION IN MONOCYTE-DERIVED MACROPHAGES