Oxidised Low-Density Lipoprotein-Induced Platelet Hyperactivity—Receptors and Signalling Mechanisms

Abstract

Dyslipidaemia leads to proatherogenic oxidative lipid stress that promotes vascular inflammation and thrombosis, the pathologies that underpin myocardial infarction, stroke, and deep vein thrombosis. These prothrombotic states are driven, at least in part, by platelet hyperactivity, and they are concurrent with the appearancxe of oxidatively modified low-density lipoproteins (LDL) in the circulation. Modified LDL are heterogenous in nature but, in a general sense, constitute a prototype circulating transporter for a plethora of oxidised lipid epitopes that act as danger-associated molecular patterns. It is well-established that oxidatively modified LDL promote platelet activation and arterial thrombosis through a number of constitutively expressed scavenger receptors, which transduce atherogenic lipid stress to a complex array of proactivatory signalling pathways in the platelets. Stimulation of these signalling events underlie the ability of modified LDL to induce platelet activation and blunt platelet inhibitory pathways, as well as promote platelet-mediated coagulation. Accumulating evidence from patients at risk of arterial thrombosis and experimental animal models of disease suggest that oxidised LDL represents a tangible link between the dyslipidaemic environment and increased platelet activation. The aim of this review is to summarise recent advances in our understanding of the pro-thrombotic signalling events induced in platelets by modified LDL ligation, describe the contribution of individual platelet scavenger receptors, and highlight potential future challenges of targeting these pathways.

The Role of CD36/GPIV in Platelet Biology

“…However, several functions of these oxLDL receptors are still elusive. 129 Nevertheless, CD36 appears as a valuable target which warrants further investigations in the field of platelet biology.…”

The Role of Potential Oxidative Biomarkers in the Prognosis of Acute Ischemic Stroke and the Exploration of Antioxidants as Possible Preventive and Treatment Options

“…If the lipid peroxidation process continues, LDL molecules could become highly oxidized to trigger macrophages activation and apoptosis [ 77 , 78 , 79 ]. Their main implication in pathological mechanisms remains the atherogenic processes, with no exception for ischemic stroke in which oxidized LDL is produced by a vicious cycle consisting of ROS production by the oxidized LDL-activated platelets [ 80 , 81 , 82 ].…”

Platelet Redox Imbalance in Hypercholesterolemia: A Big Problem for a Small Cell

“…It has been shown that oxLDL can interfere with cardinal platelet function such as adhesion [ 95 , 96 , 97 , 98 ], secretion [ 19 , 95 , 99 , 100 , 101 ], ROS generation [ 20 , 21 , 97 ], and microvesicles release, triggering a procoagulant phenotype with phosphatidylserine exposure [ 102 ], by acting synergistically with agonists, aggregation [ 103 , 104 , 105 ] even if, in other in vitro studies, low oxLDL levels seem attenuate platelet function and aggregation [ 106 , 107 , 108 , 109 ]. These contradictory findings could depend on the heterogeneous nature of oxLDL, such as the oxidized domain and extent of oxidation [ 110 ]. Actually, in vitro experiments demonstrate that the same LDL sample differently oxidized produces different products with distinct functional responses [ 111 , 112 , 113 ].…”

“…Conversely, CD36 is present on the plasma membrane both in resting and activated platelets. LOX-1 differs from CD36 also in binding oxLDL because it recognizes both mildly oxidized phospholipids and delipidated oxLDL [ 110 ]. Once on the platelet surface, LOX-1 is able to bind electronegative LDL driving the stimulation of signalling events including PI3K and MAPK/JNK which increase of p-selectin and GPIIb/IIIa expression [ 110 ].…”

“…LOX-1 differs from CD36 also in binding oxLDL because it recognizes both mildly oxidized phospholipids and delipidated oxLDL [ 110 ]. Once on the platelet surface, LOX-1 is able to bind electronegative LDL driving the stimulation of signalling events including PI3K and MAPK/JNK which increase of p-selectin and GPIIb/IIIa expression [ 110 ]. Electronegative LDLs include mildly oxidized LDL with highly electronegative fractions that increase platelet aggregation to ADP, p-selectin and integrin expression.…”