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

Abstract

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.

Figure 1

Platelet redox imbalance leading to a prothrombotic state. Major signalling pathways involved in platelet activation and increased ROS production. The imbalance between ROS production and ROS clearance causes oxidative stress and contributes to the generation of a prothrombotic state. Abbreviations: TF: tissue factor; ROS: reactive oxygen species; GPIIbIIIa: glycoprotein IIb/IIIa; PI3K: phosphoinositide 3-kinase; GPVI: glycoprotein VI; FcR γ-chain: Fc receptor γ-chain; SYK: spleen tyrosine kinase; PLC2: phospholipase C2; PIP2: phosphatidylinositol (4,5) bisphosphate; IP3: inositol trisphosphate; DAG: diacylglycerol; PKC: protein kinase C; Nox2: NADPH oxidase 2; PCSK9: proprotein convertase subtilisin/kexin type 9; CD36: cluster of differentiation 36; JNK: c-Jun N-terminal kinase; ERK5 Extracellular signal-regulated kinase 5; PLA2: phospholipase A2; AA: arachidonic acid; COX-1: cyclooxygenase 1; TxA2: thromboxane A2; PAR1/4: protease-activated receptor 1/4; RhoA: Ras homolog family member A; CDC42: cell division cycle 42; Rac1: Ras-related C3 botulinum toxin substrate 1; αIIbβ: integrin α IIb β; PS: phosphatidylserine.

Figure 2

Signaling pathways enhanced by oxLDL binding to platelet SRs and PPARα expression in dyslipidaemia. Abbreviations: LDL: low density lipoprotein; LOX-1: lectin-like oxidized low-density lipoprotein receptor-1; PI3K: phosphoinositide 3-kinase; Akt: Protein kinase B; JNK: c-Jun N-terminal kinase; oxLDL: oxidized LDL; SR-A1: scavenger receptor A1; TxA2: thromboxane A2; CD36: cluster of differentiation 36; AGEs: advanced glycation end products; SYK: spleen tyrosine kinase; Nox2: NADPH oxidase 2; PLC2: phospholipase C2; ERK Extracellular signal-regulated kinase; RhoA: Ras homolog family member A; ROS: reactive oxygen species; DAG: diacylglycerol; Casp: caspase; PKC: protein kinase C; PDE3A: phosphodiesterase 3A; PKG protein kinase G; PKA protein kinase A; cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; PPARα: peroxisome proliferator-activated receptor alpha; NO: nitric oxide; PCSK9: proprotein convertase subtilisin/kexin type 9; GPIIbIIIa: glycoprotein IIb/IIIa; PS: phosphatidylserine.

Figure 3

Effects of statins and PCSK9 inhibitors on platelet redox balance. Abbreviation: PCSK9-i: PCSK9 inhibitors; PPARα: peroxisome proliferator-activated receptor alpha; PPARγ: peroxisome proliferator-activated receptor gamma; NOS: nitric oxide synthase; GPx: glutathione peroxidase; SOD: superoxide dismutase; MAPK: mitogen-activated protein kinase; PLA2: phospholipase A2; Nox2: NADPH oxidase 2; Akt: Protein kinase B; ERK Extracellular signal-regulated kinase; cAMP: cyclic adenosine monophosphate; NO: nitric oxide; ROS: reactive oxygen species; COX-1: cyclooxygenase 1; TxA2: thromboxane A2.