161 - Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response - What is Primary? (ID 594)
- Vasily N. Sukhorukov, Russian Federation
- Nikita G. Nikiforov, Russian Federation
- Marina Kubekina, Russian Federation
- Igor A. Sobenin, Russian Federation
- Kathy K. Foxx, United States of America
- Philip Stegmaier, Germany
- Sergey Pintus, Russian Federation
- Daria Stelmashenko, Russian Federation
- Alexander Kel, Russian Federation
- Ichiro Manabe, Japan
- Yumiko Oishi, Japan
- Alexander N. Orekhov, Russian Federation
Abstract
Background and Aims
The main sources of accumulating lipids in foam cells are atherogenic modified LDL (mLDL) taking up by arterial cells in an unregulated manner bypassing the specialized LDL receptor. mLDL associates are taken up by nonspecific phagocytosis. We also used latex beads as a stimulator of macrophage phagocytotic activity. The objective was to establish whether there are common mechanisms in the interaction of macrophages with associates of mLDL and similar size non-lipid latex particles.
Methods
We used transcriptome analysis to identify regulatory pathways potentially responsible for cholesterol accumulation in human macrophages exposed to artificially modified or naturally occurring circulating atherogenic LDL.
Results
At least 12 signaling pathways were found that are similarly regulated by interaction of macrophages with multiply modified atherogenic naturally occurring LDL and with latex beads. Thus, mLDL triggers the genetic regulation characteristic of phagocytosis stimulation. We identified three genes (F2RL1, EIF2AK3, IL15) encoding inflammatory molecules and associated with these pathways. Interaction of mLDL with macrophages causes up-regulation of these genes. In two cases (EIF2AK3, IL15) of three, knock-downs completely suppressed cholesterol accumulation in macrophages. Consequently up-regulation of EIF2AK3 and IL15 promotes cholesterol accumulation.
Conclusions
These data confirmed our hypothesis based on the following: LDL undergo atherogenic modification accompanied by formation of self-associates; large LDL associates stimulate phagocytosis; as a result, proinflammatory molecules are secreted and cause or contribute to intracellular cholesterol accumulation. The hypothesis explains how the inflammatory response and cholesterol accumulation are related. Apparently inflammatory response comes first. This work was supported by the Russian Science Foundation (Grant # 20-14-00126).
