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. 2023 Oct 25;14:1254753. doi: 10.3389/fimmu.2023.1254753

Figure 5.

Figure 5

The core role of ox-LDL in the pathogenesis of atherosclerosis in patients with rheumatoid arthritis (RA). Under pathological conditions such as hypertension, hypercholesterolemia, smoking, and hyperglycemia, the vascular endothelium becomes damaged. Lipoprotein containing Apo B in plasma penetrates damaged endothelial cells into tunica intima. At the same time, the damaged endothelium expresses monocyte adhesion molecules, allowing monocytes to enter the intima and produce reactive oxygen species (ROS) to oxidize LDL to be oxidized-LDL (Ox-LDL). Ox-LDL attracts more monocytes to the site, which differentiate into macrophages. Macrophages constantly internalize ox-LDL through scavenger receptors CD36, lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), scavenger receptor class A type I/II (SR-AI/II) and class B type I(SR-BI), to accumulate as foam cells. Foam cells die, releasing their contents outside and being engulfed again by other macrophages. Ultimately, a large lesion area forms and gradually progresses into an atherosclerotic plaque. The atherosclerotic characteristics of ox-LDL can be summarized as: increasing the synthesis and secretion of adhesion molecules, chemotaxis and adhesion of monocytes, cytotoxicity to endothelial cells, enhancing foam cell formation, and increasing proliferation of smooth muscle cells. In addition, the lack of recognition of ox-LDL structure by LDLR prevents normal metabolism of LDL particles, leading to the development of atherosclerosis. In particular, under inflammatory conditions of RA, TNF, IL-6, and interferon-α (IFN-α) can enhance SR-A, LOX-1 or CD36 expression on the surface of macrophages by increasing its promoter activity in peripheral blood monocytes, thereby increasing ox-LDL uptake and enhancing foam cell formation. Elevated sdLDL in RA can promote foam cell formation and the development of atherosclerosis by regulating lipid metabolism, inducing inflammation, and enhancing endothelial injury, making itself more easily oxidized and penetrating the endothelium. Elevated Myeloperoxidase (MPO) in RA can promote LDL oxidation, leading to the formation of Mox-LDL. The clearance of Mox-LDL is reduced, exacerbating the formation of foam cells and atherosclerosis.