Abstract
Epidemiological studies confirm the high risk of ischemic events in multiple sclerosis (MS) that are associated with increased pro-thrombotic activity of blood platelets. The most potent physiological platelet agonist is thrombin, which activates platelets via cleavage of specific protease-activated receptors (PARs). Our current study is aimed to determine the potential genetics and proteomic abnormalities of PAR1 in both platelets and megakaryocytes, which may have thromboembolic consequences in the course of MS. The obtained results were correlated with the expression level of platelet and megakaryocyte transcripts for APOA1 and A2M genes encoding atherosclerosis biomarkers: apolipoprotein A1 (ApoA1) and α-2-macroglobulin (α2M), respectively. Moreover, PAR1 functionality in MS platelets was assessed by flow cytometry, determining the level of platelet–platelet and platelet–leukocyte aggregates, platelet microparticles and surface expression of P-selectin. As a PAR1 agonist, the synthetic TRAP-6 peptide was used, which made it possible to achieve platelet activation in whole blood without triggering clotting. Comparative analyses showed an elevated level of platelet activation markers in the blood of MS patients compared to controls. The mRNA expression of gene coding α2M was upregulated, whilst ApoA1 was down-regulated, both in platelets and megakaryocytes from MS patients. Furthermore, we observed an increase in both mRNA expression and surface density of PAR1 in platelets and megakaryocytes in MS compared to controls. Both the level of platelet activation markers and PAR1 expression showed a high correlation with the expression of transcripts for APOA1 and A2M genes.
Highlights
Multiple sclerosis (MS) is a major human autoimmune and degenerative disease of the central nervous system (CNS) with a variety of pathomechanisms making it a highly heterogeneous disease, considered a conglomerate of neurological syndromes [1]
As a result of our analysis, we demonstrated an explicit increase in the formation of platelet aggregates (PAGs), platelet-derived microparticles (PMPs), platelet-leukocyte aggregates (PLAs), as well as a higher expression of surface P-selectin (CD62P) in SP MS patients compared to a control group, both in non-stimulated and TRAP-6-stimulated blood platelets
We showed that in quiescent platelets from SP MS patients there was an elevated level of PAGs (Figure 1A), PMPs (1.5-fold vs. control, p < 0.0001) (Figure 1B), PLAs (2-fold vs. control, p < 0.0001) (Figure 1C), as well as the higher surface expression of P-selectin (Figure 1D)
Summary
Multiple sclerosis (MS) is a major human autoimmune and degenerative disease of the central nervous system (CNS) with a variety of pathomechanisms making it a highly heterogeneous disease, considered a conglomerate of neurological syndromes [1]. Epidemiological studies have proved that comorbidities such as ischemic stroke, atherosclerosis, thrombosis, and myocardial infarction have been associated with increased mortality in patients with MS, especially in the progressive stage of MS [4,5,6]. Recent meta-analyses and cohort studies concluded that MS is declared to be associated with cardiovascular disease (CVD) due to both thrombin upregulation and blood platelet pro-thrombotic over-activity [9,10,11]. The chronic activation of blood platelets in SP MS, as expressed by high levels of activation markers, altered mitochondrial function, and increased platelet reactivity, has been proven in our previous studies to focus exclusively on the progressive stage of MS, characterized with an especially high risk of CVD [15,16,17]. Our findings have demonstrated changes in the protein profile, manifesting an enhanced level of blood coagulation factors [18]
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