The imbalance between reactive oxygen species (ROS) synthesis and their scavenging by anti-oxidant defences is the common soil of many disorders, including hypercholesterolemia. Platelets, the smallest blood cells, are deeply involved in the pathophysiology of occlusive arterial thrombi associated with myocardial infarction and stroke. A great deal of evidence shows that both increased intraplatelet ROS synthesis and impaired ROS neutralization are implicated in the thrombotic process. Hypercholesterolemia is recognized as cause of atherosclerosis, cerebro- and cardiovascular disease, and, closely related to this, is the widespread acceptance that it strongly contributes to platelet hyperreactivity via direct oxidized LDL (oxLDL)-platelet membrane interaction via scavenger receptors such as CD36 and signaling pathways including Src family kinases (SFK), mitogen-activated protein kinases (MAPK), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In turn, activated platelets contribute to oxLDL generation, which ends up propagating platelet activation and thrombus formation through a mechanism mediated by oxidative stress. When evaluating the effect of lipid-lowering therapies on thrombogenesis, a large body of evidence shows that the effects of statins and proprotein convertase subtilisin/kexin type 9 inhibitors are not limited to the reduction of LDL-C but also to the down-regulation of platelet reactivity mainly by mechanisms sensitive to intracellular redox balance. In this review, we will focus on the role of oxidative stress-related mechanisms as a cause of platelet hyperreactivity and the pathophysiological link of the pleiotropism of lipid-lowering agents to the beneficial effects on platelet function.
Keywords: hypercholesterolemia; oxidative stress; platelet activation; proprotein convertase subtilisin/kexin type 9; statins.