title: Inhibition of Platelet GPVI Protects Against Myocardial Ischemia-Reperfusion Injury.
abstract: OBJECTIVE
  The objective of this study was to investigate the effects of platelet inhibition on myocardial ischemia-reperfusion (IR) injury.
  
  
  RESULTS
  Timely restoration of coronary blood flow after myocardial infarction is indispensable but leads to additional damage to the heart (myocardial IR injury). Microvascular dysfunction contributes to myocardial IR injury. We hypothesized that platelet activation during IR determines microvascular perfusion and thereby the infarct size in the reperfused myocardium. The 3 phases of thrombus formation were analyzed by targeting individual key platelet-surface molecules with monoclonal antibody derivatives: (1) adhesion (anti-glycoprotein [GP]-Ib), (2) activation (anti-GPVI), and (3) aggregation (anti-GPIIbIIIa) in a murine in vivo model of left coronary artery ligation (30 minutes of ischemia followed by 24 hours of reperfusion). Infarct sizes were determined by Evans Blue/2,3,5-triphenyltetrazolium chloride staining, infiltrating neutrophils by immunohistology. Anti-GPVI treatment significantly reduced infarct size versus control, whereas anti-GPIb or anti-GPIIbIIIa antibody fragments showed no significant differences. Mechanistically, anti-GPVI antibody-mediated reduction of infarct size was not because of impaired Ca(2+) signaling or platelet degranulation because mice deficient in store-operated calcium channels (stromal interaction molecule 1, ORAI1), α-granules (Nbeal2(-/-)), and dense granule release (Unc13d(-/-)) had similar infarct sizes as control animals. Protective effects of anti-GPVI treatment were accompanied by improved microperfusion. Leukocyte infiltration was reduced in both anti-GPVI and anti-GPIb-treated IR mice.
  
  
  CONCLUSIONS
  Inhibition of platelet activation by an anti-GPVI antibody, but not inhibition of platelet adhesion or aggregation by an anti-GPIb or anti-GPIIbIIIa antibody significantly reduces infarct size. The reduction of the infarct size is primarily based on an improved microperfusion after anti-GPVI antibody treatment.
authors.affiliation: From the Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (C.P., D.M., A.-P.A.-L., W.H., P.N., U.H., S.F.); Hospital Pharmacy, Jena University Hospital, Jena, Germany (D.M.); Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany (U.H., S.F.); Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany (C.D., V.L., B.N.); Division of Newborn Medicine, Boston Children's Hospital, Boston (V.L.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Christina
authors.initials: C
authors.lastname: Pachel
authors.affiliation: From the Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (C.P., D.M., A.-P.A.-L., W.H., P.N., U.H., S.F.); Hospital Pharmacy, Jena University Hospital, Jena, Germany (D.M.); Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany (U.H., S.F.); Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany (C.D., V.L., B.N.); Division of Newborn Medicine, Boston Children's Hospital, Boston (V.L.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Denise
authors.initials: D
authors.lastname: Mathes
authors.affiliation: From the Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (C.P., D.M., A.-P.A.-L., W.H., P.N., U.H., S.F.); Hospital Pharmacy, Jena University Hospital, Jena, Germany (D.M.); Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany (U.H., S.F.); Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany (C.D., V.L., B.N.); Division of Newborn Medicine, Boston Children's Hospital, Boston (V.L.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Anahi-Paula
authors.initials: AP
authors.lastname: Arias-Loza
authors.affiliation: From the Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (C.P., D.M., A.-P.A.-L., W.H., P.N., U.H., S.F.); Hospital Pharmacy, Jena University Hospital, Jena, Germany (D.M.); Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany (U.H., S.F.); Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany (C.D., V.L., B.N.); Division of Newborn Medicine, Boston Children's Hospital, Boston (V.L.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Wolfram
authors.initials: W
authors.lastname: Heitzmann
authors.affiliation: From the Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (C.P., D.M., A.-P.A.-L., W.H., P.N., U.H., S.F.); Hospital Pharmacy, Jena University Hospital, Jena, Germany (D.M.); Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany (U.H., S.F.); Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany (C.D., V.L., B.N.); Division of Newborn Medicine, Boston Children's Hospital, Boston (V.L.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Peter
authors.initials: P
authors.lastname: Nordbeck
authors.affiliation: From the Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (C.P., D.M., A.-P.A.-L., W.H., P.N., U.H., S.F.); Hospital Pharmacy, Jena University Hospital, Jena, Germany (D.M.); Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany (U.H., S.F.); Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany (C.D., V.L., B.N.); Division of Newborn Medicine, Boston Children's Hospital, Boston (V.L.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Carsten
authors.initials: C
authors.lastname: Deppermann
authors.affiliation: From the Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (C.P., D.M., A.-P.A.-L., W.H., P.N., U.H., S.F.); Hospital Pharmacy, Jena University Hospital, Jena, Germany (D.M.); Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany (U.H., S.F.); Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany (C.D., V.L., B.N.); Division of Newborn Medicine, Boston Children's Hospital, Boston (V.L.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Viola
authors.initials: V
authors.lastname: Lorenz
authors.affiliation: From the Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (C.P., D.M., A.-P.A.-L., W.H., P.N., U.H., S.F.); Hospital Pharmacy, Jena University Hospital, Jena, Germany (D.M.); Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany (U.H., S.F.); Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany (C.D., V.L., B.N.); Division of Newborn Medicine, Boston Children's Hospital, Boston (V.L.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hofmann
authors.affiliation: From the Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (C.P., D.M., A.-P.A.-L., W.H., P.N., U.H., S.F.); Hospital Pharmacy, Jena University Hospital, Jena, Germany (D.M.); Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany (U.H., S.F.); Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany (C.D., V.L., B.N.); Division of Newborn Medicine, Boston Children's Hospital, Boston (V.L.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.).
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.affiliation: From the Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (C.P., D.M., A.-P.A.-L., W.H., P.N., U.H., S.F.); Hospital Pharmacy, Jena University Hospital, Jena, Germany (D.M.); Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany (U.H., S.F.); Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany (C.D., V.L., B.N.); Division of Newborn Medicine, Boston Children's Hospital, Boston (V.L.); and Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany (U.H., S.F.). stefan.frantz@uk-halle.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Frantz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI
keywords: GPVI collagen receptor; microperfusion; myocardial infarction; myocardial reperfusion injury; platelet inhibition