5-HT 2A Receptor and 5-HT Degradation Play a Crucial Role in Atherosclerosis by Modulating Macrophage Foam Cell Formation, Vascular Endothelial Cell Inflammation, and Hepatic Steatosis.

Aim: Previously, we found that diabetes-related liver dysfunction is due to activation of the 5-HT _2A receptor (5-HT _2A R) and increased synthesis and degradation of 5-HT. Here, we investigated the role of 5-HT in the development of atherosclerosis.
Methods: The study was conducted using high-fat diet-fed male ApoE ^-/- mice, THP-1 cell-derived macrophages, and HUVECs. Protein expression and biochemical indexes were determined by Western blotting and quantitative analysis kit, respectively. The following staining methods were used: oil red O staining (showing atherosclerotic plaques and intracellular lipid droplets), immunohistochemistry (showing the expression of 5-HT _2A R, 5-HT synthase, and CD68 in the aortic wall), and fluorescent probe staining (showing intracellular ROS).
Results: In addition to improving hepatic steatosis, insulin resistance, and dyslipidemia, co-treatment with a 5-HT synthesis inhibitor and a 5-HT _2A R antagonist significantly suppressed the formation of atherosclerotic plaques and macrophage infiltration in the aorta of ApoE ^-/- mice in a synergistic manner. Macrophages and HUVECs exposed to oxLDL or palmitic acid in vitro showed that activated 5-HT _2A R regulated TG synthesis and oxLDL uptake by activating PKCε, resulting in formation of lipid droplets and even foam cells; ROS production was due to the increase of both intracellular 5-HT synthesis and mitochondrial MAO-A-catalyzed 5-HT degradation, which leads to the activation of NF-κB and the release of the inflammatory cytokines TNF-α and IL-1β from macrophages and HUVECs as well as MCP-1 release from HUVECs.
Conclusion: Similar to hepatic steatosis, the pathogenesis of lipid-induced atherosclerosis is associated with activation of intracellular 5-HT _2A R, 5-HT synthesis, and 5-HT degradation.