Study on the Interaction Between Oxidized Low-Density Lipoprotein and Platelets in Atherosclerosis

LDL Binding Sites on Platelets

During the inflammatory and oxidative processes of plaque formation, the modification of LDL by phospholipid oxidation leads to the production of prethrombotic ox-LDL. Dyslipidemia induces the production of ox-LDL, which promotes platelet activation by binding to platelet surface scavenger receptors CD36 and LOX-1.

Class B scavenger receptor CD36 leukocyte differentiation antigen 36 (cluster of differentiation 36, CD36) belongs to the B-type scavenger receptor (SR) family. It is a highly glycosylated, 88kU multifunctional single-chain transmembrane protein that is constitutively expressed on a variety of cell types including platelets and participates in cholesterol and lipoprotein metabolism. SR binds to a variety of ligands, including LDL, ox-LDL, acetylated LDL, and modified high-density lipoproteins (HDL), and plays an important role in the formation and progression of AS plaques. Studies have shown that the binding of ox-LDL to the CD36 receptor triggers the platelet activation signaling pathway, inducing P-selectin expression and integrin αIIbβ3 activation. The binding of ox-LDL to CD36 can form a platelet-leukocyte complex through P-selectin and cross-link adjacent platelets through fibrinogen.

The E-class scavenger receptor LOX-1 lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was originally described as a type 2 transmembrane glycoprotein with a size of 50 kU in endothelial cells. There is a long extracellular region at the C-terminus of its amino acid sequence. This structure belongs to the C-class hemagglutinin family and is the binding region for ligands such as ox-LDL. The sequence presents a dynamic equilibrium helical structure. This highly conserved structure helps LOX-1 recognize ox-LDL and trigger downstream signaling pathways, thereby mediating the uptake of ox-LDL by endothelial cells and platelets. LOX-1 is also expressed in platelets and can enhance platelet activation, endothelial cell adhesion, and ADP-mediated aggregation, thereby promoting thrombosis. In cardiomyocytes, LOX-1 has been shown to be associated with the development of cardiac fibrosis and cardiomyocyte apoptosis, which is the main determinant of cardiac recovery after ischemic injury. The binding of ox-LDL to LOX-1 leads to the activation of αIIbβ3 and α2β1, which are fibrinogen and collagenogen receptors, respectively, and are essential for thrombosis. Dendritic cells (DCs), as the core coordinators of the immune system response, play a key regulatory role in the occurrence and development of AS.

The Role of Activated Platelets and ox-LDL in AS

Increased platelet activation and elevated ox-LDL concentrations are important pathophysiological mechanisms leading to the development of AS. Activated platelets interact with endothelial cells and change the chemotaxis and adhesion of endothelial cells, which is a key initial step in the formation of AS. AS often occurs at arterial bends and bifurcations with turbulent blood flow. Changes in hemodynamics here increase plaque instability and induce plaque rupture. Plaque rupture leads to platelet activation in the blood and activation of the coagulation pathway cascade. Platelets are not only the first circulating blood cells to adhere to the site of vascular damage, but also have the ability to migrate to find bacteria. Platelet function and its interaction with LDL determine the stability of plaques. Platelet factor 4 (PF4orCXCL4) is conducive to platelet activation and migration, and enhances the uptake of ox-LDL by macrophages, promotes the formation of foam cells and causes the development of the lipid core of AS plaques. CXCL4 and ox-LDL were found to co-localize in macrophage-derived foam cells in AS lesions. This mechanism may promote vascular lipid deposition. Reducing the generation of foam cells induced by activated platelets may be one of the potential mechanisms of the pleiotropic effects of statins. Migration inhibitory factor (MIF) is a newly discovered chemokine produced by macrophages and endothelial cells in platelet secretory granules. This molecule is related to the adhesion and migration of monocytes into AS lesions. Platelets stimulated by ox-LDL can not only enter the plaque through the site of vascular damage, but also migrate to the core of the plaque through the activated monolayer of endothelial cells under the premise of signals provided by circulating monocytes. Activated platelets and ox-LDL exert pro-inflammatory and pro-coagulant effects on a variety of vascular cells (neutrophils, monocytes/macrophages, smooth muscle cells, endothelial cells and platelets), and the interaction between them can also affect endothelial cell regeneration and foam cell generation, all of which contribute to the occurrence and development of AS.