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The Molecular Aspects of Disturbed Platelet Activation through ADP/P2Y12 Pathway in Multiple Sclerosis
Angela Dziedzic1, Elzbieta Miller2, Joanna Saluk-Bijak1
1Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
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.
Insights
Patients with secondary-progressive multiple sclerosis (SP MS) exhibit heightened platelet reactivity due to increased P2Y12 receptor expression. This finding may explain their elevated risk of ischemic events and suggests new therapeutic targets.
Area of Science:
- Cardiovascular Research
- Neuroimmunology
- Hematology
Background:
- Secondary-progressive multiple sclerosis (SP MS) patients face a high risk of ischemic events.
- This risk is linked to increased pro-thrombotic activity in platelets.
- Platelet abnormalities may contribute to thromboembolism in MS.
Purpose of the Study:
- To investigate molecular abnormalities in platelet P2Y12 receptor expression and function in SP MS.
- To determine if P2Y12 receptor alterations contribute to increased thromboembolism risk in MS patients.
- To explore the role of the PAR1 signaling pathway in P2Y12 expression.
Main Methods:
- Comparative analysis of platelet reactivity to adenosine diphosphate (ADP) in SP MS patients versus controls.
- Quantification of P2RY12 gene mRNA expression in platelets and megakaryocytes.
- Assessment of P2Y12 receptor density on the platelet surface.
- Correlation analysis between P2Y12 expression and platelet activation markers induced by TRAP-6 (PAR1 agonist).
Main Results:
- SP MS patients demonstrated enhanced platelet reactivity to ADP compared to controls.
- Increased P2RY12 mRNA expression was observed in platelets and megakaryocytes of SP MS patients.
- Elevated P2Y12 receptor density was found on the surface of platelets from SP MS patients.
- Correlation analysis explored the impact of PAR1 signaling on P2Y12 expression.
Conclusions:
- Reinforced P2Y12 receptor expression, genetically or phenotypically, may underlie the heightened ischemic event risk in SP MS.
- Understanding these molecular mechanisms can guide the development of targeted prevention and treatment strategies for cardiovascular complications in MS.
- This research highlights P2Y12 receptor as a potential therapeutic target to mitigate thromboembolic risks in SP MS.
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