GPVI surface expression and signalling pathway activation are increased in platelets from obese patients: Elucidating potential anti-atherothrombotic targets in obesity
| Autor: | Núñez Barrachina, María, Sueiro, Aurelio M., Izquierdo Berjano, Irene, Hermida Nogueira, Lidia, Guitián Fernández, Esteban, Casanueva Freijo, Felipe, Farndale, Richard W., Masaaki, Moroi, Jung, Stephanie M., Pardo Pérez, María, García Alonso, Ángel |
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| Přispěvatelé: | Farndale, Richard [0000-0001-6130-8808], Apollo - University of Cambridge Repository, 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 |
| Rok vydání: | 2019 |
| Předmět: |
Platelets
Proteomics Adult Blood Platelets Male Drug targets Adolescent Platelet Aggregation Phospholipase C gamma GPVI signalling Platelet Membrane Glycoproteins Platelet Activation Article Body Mass Index Up-Regulation Young Adult Case-Control Studies Humans Female Obesity Phosphorylation SFK-Mediated signalling pathways Signal Transduction |
| Zdroj: | Atherosclerosis Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela instname |
| Popis: | 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 CRP-activated 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. Graphical abstract Image 1 Highlights • Higher expression of the active form of Src (pTyr418) in obese patients platelets. • Increased aggregation levels of obese platelets in response to GPVI activation. • GPVI-activated platelets show higher levels of tyr-phosphorylated PLCγ2 in obesity. • Higher surface expression levels of GPVI in obese platelets, correlating with BMI. |
| Databáze: | OpenAIRE |
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