title: Platelet Gi protein Gαi2 is an essential mediator of thrombo-inflammatory organ damage in mice.
abstract: Platelets are crucial for hemostasis and thrombosis and exacerbate tissue injury following ischemia and reperfusion. Important regulators of platelet function are G proteins controlled by seven transmembrane receptors. The Gi protein Gα(i2) mediates platelet activation in vitro, but its in vivo role in hemostasis, arterial thrombosis, and postischemic infarct progression remains to be determined. Here we show that mice lacking Gα(i2) exhibit prolonged tail-bleeding times and markedly impaired thrombus formation and stability in different models of arterial thrombosis. We thus generated mice selectively lacking Gα(i2) in megakaryocytes and platelets (Gna(i2)(fl/fl)/PF4-Cre mice) and found bleeding defects comparable to those in global Gα(i2)-deficient mice. To examine the impact of platelet Gα(i2) in postischemic thrombo-inflammatory infarct progression, Gna(i2)(fl/fl)/PF4-Cre mice were subjected to experimental models of cerebral and myocardial ischemia/reperfusion injury. In the model of transient middle cerebral artery occlusion stroke Gna(i2)(fl/fl)/PF4-Cre mice developed significantly smaller brain infarcts and fewer neurological deficits than littermate controls. Following myocardial ischemia, Gna(i2)(fl/fl)/PF4-Cre mice showed dramatically reduced reperfusion injury which correlated with diminished formation of the ADP-dependent platelet neutrophil complex. In conclusion, our data provide definitive evidence that platelet Gα(i2) not only controls hemostatic and thrombotic responses but also is critical for the development of ischemia/reperfusion injury in vivo.
authors.affiliation: Department of Pharmacology and Experimental Therapy and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, 72074 Tubingen, Germany;
authors.forename: Vasudharani
authors.initials: V
authors.lastname: Devanathan
authors.affiliation: Department of Experimental Biomedicine, University Hospital, Rudolf Virchow Center, and.
authors.forename: Ina
authors.initials: I
authors.lastname: Hagedorn
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, 72076 Tubingen, Germany;
authors.forename: David
authors.initials: D
authors.lastname: Köhler
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Düsseldorf University, 40225 Dusseldorf, Germany; and.
authors.forename: Katja
authors.initials: K
authors.lastname: Pexa
authors.affiliation: Department of Experimental Biomedicine, University Hospital, Rudolf Virchow Center, and.
authors.forename: Deya
authors.initials: D
authors.lastname: Cherpokova
authors.affiliation: Department of Neurology, University of Würzburg, 97080 Wurzburg, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Düsseldorf University, 40225 Dusseldorf, Germany; and.
authors.forename: Madhurendra
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, 72076 Tubingen, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenberger
authors.affiliation: Department of Neurology, University of Würzburg, 97080 Wurzburg, Germany;
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
authors.affiliation: Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27009 birnbau1@gmail.com bernd.nuernberg@uni-tuebingen.de.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Düsseldorf University, 40225 Dusseldorf, Germany; and.
authors.forename: Roland P
authors.initials: RP
authors.lastname: Piekorz
authors.affiliation: Department of Pharmacology and Experimental Therapy and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, 72074 Tubingen, Germany;
authors.forename: Sandra
authors.initials: S
authors.lastname: Beer-Hammer
authors.affiliation: Department of Experimental Biomedicine, University Hospital, Rudolf Virchow Center, and.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.affiliation: Department of Pharmacology and Experimental Therapy and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, 72074 Tubingen, Germany; birnbau1@gmail.com bernd.nuernberg@uni-tuebingen.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000172:deficiency / Q000378:metabolism*; D015151:Immunoblotting; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology*; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D015539:Platelet Activation / Q000502:physiology*; D015427:Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control; D013927:Thrombosis / Q000503:physiopathology*
chemical_list: D051960:GTP-Binding Protein alpha Subunit, Gi2; C498016:Gnai2 protein, mouse
keywords: G proteins; P2Y12 receptor; ischemia reperfusion injury; platelets; thrombosis