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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Fecha de publicación
2019Título de revista
ATHEROSCLEROSIS
Tipo de contenido
Artigo
DeCS
estudios de casos y controles | glicoproteínas de la membrana plaquetaria | fosforilación | regulación positiva | agregación plaquetaria | adulto | transducción de señales | activación plaquetaria | fosfolipasa C gamma | adulto joven | obesidad | humanos | proteómica | índice de masa corporal | adolescente | plaquetasMeSH
Adult | Platelet Activation | Platelet Aggregation | Adolescent | Obesity | Phospholipase C gamma | Platelet Membrane Glycoproteins | Up-Regulation | Body Mass Index | Signal Transduction | Proteomics | Blood Platelets | Humans | Young Adult | Phosphorylation | Case-Control StudiesResumen
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 alphaIIb 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 PLCgamma2 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.
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