LDL-Cholesterol and Platelets: Insights into Their Interactions in Atherosclerosis

Abstract

Atherosclerosis and its complications, including acute coronary syndromes, are the major cause of death worldwide. The two most important pathophysiological mechanisms underlying atherosclerosis include increased platelet activation and increased low-density lipoproteins (LDL) concentration. In contrast to LDL, oxidized (ox)-LDL have direct pro-thrombotic properties by functional interactions with platelets, leading to platelet activation and favoring thrombus formation. In this review, we summarize the currently available evidence on the interactions between LDL-cholesterol and platelets, which are based on (i) the presence of ox-LDL-binding sites on platelets, (ii) generation of ox-LDL by platelets and (iii) the role of activated platelets and ox-LDL in atherosclerosis. In addition, we elaborate on the clinical implications of these interactions, including development of the new therapeutic possibilities. The ability to understand and modulate mechanisms governing interactions between LDL-cholesterol and platelets may offer new treatment strategies for atherosclerosis prevention.

Antiplatelet Effects of PCSK9 Inhibitors in Primary Hypercholesterolemia

“…Platelet activation in hypercholesterolemic states occurs through several mechanisms, including: (i) scavenger receptor cluster of differentiation (CD)36, (ii) scavenger receptor lectin-like ox-LDL receptor-1 (LOX-1), and (iii) LDL-C triggered platelet membrane composition changes [ 34 ]. The mechanisms of platelet activation by LDL are shown in Figure 2 .…”

“…It is a ligand for a number of particles, such as thrombospondin-1, ox-LDL, fatty acids, microbial diacyloglycerides, and many others [ 35 , 37 , 38 ]. Previous studies have shown that the interaction of CD36 with ox-LDL triggers signaling pathways that activate platelets, inducing the expression of P-selectin and the activation of integrin α IIb β 3 (the receptor for fibrinogen), therefore facilitating the formation of platelet–leukocyte complexes via P-selectin and the cross-linking of adjacent platelets via fibrinogen [ 34 , 39 ]. The ox-LDL–CD36 interaction was shown to trigger platelet hyperreactivity via Src family kinases, Vav-guanine nucleotide exchange factors, cyclic guanosine monophosphate (cGMP), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, producing reactive forms of oxygen and leading to a vicious circle of LDL oxidation and platelet activation [ 40 , 41 ].…”

“…The binding of ox-LDL to CD36 also induces the release of various chemokines, such as monocyte chemotactic protein-1 and the interleukin 1β precursor, leading to the progression of atherosclerosis [ 42 , 43 ]. CD36 activation is also an important factor contributing to ox-LDL platelet internalization and foam cell formation [ 34 , 43 ].…”

“…It is a class E scavenger receptor involved in the regulation of ox-LDL uptake by endothelial cells and platelets [ 44 , 45 ]. Contrary to the native expression of CD36, LOX-1 expression is atheroma-related [ 34 , 46 ]. Binding between ox-LDL and LOX-1 leads to the activation of integrins α IIb β 3 and α 2 β 1 , which results in platelet shape change and aggregation, contributing to thrombus formation [ 44 , 45 ].…”

Statins in COVID-19 Therapy

“…In the absence of a specific treatment, it is crucial to establish the effect of co-administered medications in patients with COVID-19. Among cardiovascular medications, statins play a crucial role both in primary and secondary prevention of cardiovascular events [ 14 ]. Moreover, statins have well-established pleiotropic effects, including improvement of endothelial dysfunction, antioxidant properties, atherosclerotic plaque stabilization, and inhibition of inflammatory responses [ 14 ].…”