title: Impaired alpha(IIb)beta(3) integrin activation and shear-dependent thrombus formation in mice lacking phospholipase D1.
abstract: Platelet aggregation is essential for hemostasis but can also cause myocardial infarction and stroke. A key but poorly understood step in platelet activation is the shift of the principal adhesive receptor, alpha(IIb)beta(3) integrin, from a low- to high-affinity state for its ligands, a process that enables adhesion and aggregation. In response to stimulation of heterotrimeric guanosine triphosphate-binding protein or immunoreceptor tyrosine-based activation motif-coupled receptors, phospholipases cleave membrane phospholipids to generate lipid and soluble second messengers. An essential role in platelet activation has been established for phospholipase C (PLC) but not for PLD and its product phosphatidic acid. Here, we report that platelets from Pld1(-/-) mice displayed impaired alpha(IIb)beta(3) integrin activation in response to major agonists and defective glycoprotein Ib-dependent aggregate formation under high shear conditions. These defects resulted in protection from thrombosis and ischemic brain infarction without affecting tail bleeding times. These results indicate that PLD1 may be a critical regulator of platelet activity in the setting of ischemic cardiovascular and cerebrovascular events.
authors.affiliation: University Clinic Würzburg and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
authors.forename: Margitta
authors.initials: M
authors.lastname: Elvers
authors.forename: David
authors.initials: D
authors.lastname: Stegner
authors.forename: Ina
authors.initials: I
authors.lastname: Hagedorn
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.forename: Attila
authors.initials: A
authors.lastname: Braun
authors.forename: Marijke E J
authors.initials: ME
authors.lastname: Kuijpers
authors.forename: Michael
authors.initials: M
authors.lastname: Boesl
authors.forename: Qin
authors.initials: Q
authors.lastname: Chen
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Heemskerk
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
authors.forename: Michael A
authors.initials: MA
authors.lastname: Frohman
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000201:enzymology*; D020520:Brain Infarction / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis / Q000201:enzymology* / Q000235:genetics; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010738:Type C Phospholipases; D010739:Phospholipase D; C106801:phospholipase D1