The Molecular Aspects of Disturbed Platelet Activation through ADP/P2Y12 Pathway in Multiple Sclerosis.

Angela Dziedzic,Michal Bijak,Elzbieta Miller,Joanna Saluk-Bijak,Marta Niwald

doi:10.3390/ijms22126572

Abstract

Epidemiological studies confirm a high risk of ischemic events in secondary-progressive multiple sclerosis (SP MS) patients, directly associated with an increased level of pro-thrombotic activity of platelets. Our work aimed to verify potential molecular abnormalities of the platelet P2Y12 receptor expression and functionality as a cause of an increased risk of thromboembolism observed in the course of MS. We have demonstrated an enhanced platelet reactivity in response to adenosine diphosphate (ADP) in SP MS relative to controls. We have also shown an increased mRNA expression for the P2RY12 gene in both platelets and megakaryocytes, as well as enhanced density of these receptors on the platelet surface. We postulate that one of the reasons for the elevated risk of ischemic events observed in MS may be a genetically or phenotypically reinforced expression of the platelet P2Y12 receptor. In order to analyze the effect of the PAR1 (protease activated receptor type 1) signaling pathway on the expression level of P2Y12, we also analyzed the correlation parameters between P2Y12 expression and the markers of platelet activation in MS induced by selective PAR1 agonist (thrombin receptor activating peptide-6, TRAP-6). Identifying the molecular base responsible for the enlarged pro-thrombotic activity of platelets in SP MS could contribute to the implementation of prevention and targeted treatment, reducing the development of cardiovascular disorders in the course of the disease.

Highlights

Blood platelets belong to principal hemostatic cells, but besides participating in thrombotic mechanisms, they play a key role in inflammation, including neuroinflammatory events
As a result of our cytometric analysis, we demonstrated an explicit increase in the percentage of PAGs, PLAs, and PMPs, as well as a higher expression of surface P-selectin in secondary-progressive multiple sclerosis (SP multiple sclerosis (MS)) patients compared to control in adenosine diphosphate (ADP)-stimulated blood platelets
An irreversible platelet aggregation mediated by both thrombin receptors PAR1 and PAR4 is largely dependent on stimulation of the P2Y12/Gi pathway by ADP released from platelets [46,47]

Summary

Introduction

Blood platelets belong to principal hemostatic cells, but besides participating in thrombotic mechanisms, they play a key role in inflammation, including neuroinflammatory events. The same molecular mechanisms that underlie the hemostatic function of platelets facilitate the participation of these cells in other physiological and pathological processes due to the cooperation with immunologically competent cells in inflammatory and immune responses [2]. The presence of constitutive receptors involves multiple feedback loops and induces activation-dependent receptors, which, like P-selectin, support cross-talk between platelets and endothelial and immune cells [5]. The pathomechanism of MS involves a disruption of the blood–brain barrier (BBB), which is induced by the enormous influx of inflammatory cells. Their recruitment, and in consequence, a pro-inflammatory stimulation of microglial cells, results in the destruction of the myelin sheath, accelerating the formation of demyelinating lesions [10]

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