GPVI surface expression and signalling pathway activation are increased in platelets from obese patients: Elucidating potential anti-atherothrombotic targets in obesity
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|Title:||GPVI surface expression and signalling pathway activation are increased in platelets from obese patients: Elucidating potential anti-atherothrombotic targets in obesity
|Author:||Núñez Barrachina, María
Sueiro, Aurelio M.
Izquierdo Berjano, Irene
Hermida Nogueira, Lidia
Guitián Fernández, Esteban
Casanueva Freijo, Felipe
Farndale, Richard W.
Jung, Stephanie M.
Pardo Pérez, María
García Alonso, Ángel
|Affiliation:||Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas
Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica
|Subject:||Platelets | Obesity | Proteomics | GPVI signalling | SFK-Mediated signalling pathways | Drug targets ||
|Date of Issue:||2019
|Citation:||Barrachina, M. N., Sueiro, A. M., Izquierdo, I., Hermida-Nogueira, L., Guitián, E., Casanueva, F. F., . . . García, Á. (2019). GPVI surface expression and signalling pathway activation are increased in platelets from obese patients: Elucidating potential anti-atherothrombotic targets in obesity. Atherosclerosis, 281, 62-70. doi:10.1016/j.atherosclerosis.2018.12.023
|Abstract:||Background and aims: Platelets play a fundamental role in the increased atherothrombotic risk related to central obesity since they show hyperactivation and lower sensitivity to antiplatelet therapy in obese patients. The main goal of this study was to identify platelet biomarkers related to the risk of atherothrombosis in obese patients, confirm platelet activation levels in these patients, and identify altered activation pathways. Methods: Platelets were obtained from cohorts of obese patients and age- and sex-matched lean controls. Biochemical and proteome analyses were done by two-dimensional differential in-gel electrophoresis (2D-DIGE), mass spectrometry, and immunoblotting. Functional and mechanistic studies were conducted with aggregation assays and flow cytometry. Results: We confirmed an up-regulation of αIIb and fibrinogen isoforms in platelets from obese patients. A complementary platelet aggregation approach showed platelets from obese patients are hyper-reactive in response to collagen and collagen-related peptide (CRP), revealing the collagen receptor Glycoprotein VI (GPVI) signalling as one of the altered pathways. We also found the active form of Src (pTyr418) is up-regulated in platelets from obese individuals, which links proteomics to aggregation data. Moreover, we showed that CRPactivated platelets present higher levels of tyrosine phosphorylated PLCγ2 in obese patients, confirming alterations in GPVI signalling. In line with the above, flow cytometry studies show higher surface expression levels of total GPVI and GPVI-dimer in obese platelets, both correlating with BMI. Conclusions: Our results suggest a higher activation state of SFKs-mediated signalling pathways in platelets from obese patients, with a primary involvement of GPVI signalling.|
|Rights:||© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/)