title: Alteration of platelet GPVI signaling in ST-elevation myocardial infarction patients demonstrated by a combination of proteomic, biochemical, and functional approaches.
abstract: The platelet-specific collagen receptor glycoprotein VI (GPVI) is critical for the formation of arterial thrombosis in vivo. We analyzed GPVI-activated platelets from ST-elevation myocardial infarction (STEMI) patients and matched stable coronary artery disease (SCAD) controls in order to provide novel clues on the degree of involvement of GPVI signaling in the acute event. Firstly, platelets were isolated from systemic venous blood and activated with the GPVI specific agonist CRP (collagen-related peptide). STEMI and SCAD samples were compared by a phosphoproteomics approach. Validations were by immunoblotting in systemic and intracoronary blood from independent cohorts of patients. Twenty-six differentially regulated proteins were identified when comparing CRP-activated systemic platelets from STEMI and SCAD patients, 4 of which were selected for validation studies: PLCɣ2, G6f, SLP-76, and Dok-2. Immunoblot analyses showed these four proteins had higher tyrosine phosphorylation levels in response to CRP in platelets from STEMI patients, being these levels more pronounced at the culprit site of coronary artery occlusion. Moreover, platelet aggregation studies showed a higher response to GPVI agonists in STEMI patients compared to SCAD controls. In conclusion, we show an altered activation state of GPVI signaling in STEMI patients, confirming this receptor as a promising anti-thrombotic target for myocardial infarction.
authors.affiliation: Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.|Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Vélez
authors.affiliation: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain.|Cardiology Department and Coronary Care Unit, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
authors.forename: Raymundo
authors.initials: R
authors.lastname: Ocaranza-Sánchez
authors.affiliation: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain.|Cardiology Department and Coronary Care Unit, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: López-Otero
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
authors.forename: Lilian
authors.initials: L
authors.lastname: Grigorian-Shamagian
authors.affiliation: Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.|Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Rosa
authors.affiliation: Mass Spectrometry and Proteomic Unit, Rede de Infraestructuras de Apoio á Investigación e ao Desenvolvemento Tecnolóxico (RIAIDT), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Guitián
authors.affiliation: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain.|Cardiology Department and Coronary Care Unit, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: García-Acuña
authors.affiliation: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain.|Cardiology Department and Coronary Care Unit, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
authors.forename: José Ramón
authors.initials: JR
authors.lastname: González-Juanatey
authors.affiliation: Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.|Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: García
mesh_terms: D000368:Aged; D001792:Blood Platelets / Q000378:metabolism*; D015331:Cohort Studies; D003094:Collagen / Q000737:chemistry; D003324:Coronary Artery Disease / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D015539:Platelet Activation; D010974:Platelet Aggregation; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D040901:Proteomics; D000072657:ST Elevation Myocardial Infarction / Q000378:metabolism*; D015398:Signal Transduction; D013927:Thrombosis / Q000378:metabolism
chemical_list: D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D003094:Collagen