Impaired alpha(IIb)beta(3) integrin activation and shear-dependent thrombus formation in mice lacking phospholipase D1.
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.
Elvers
Margitta
M
University Clinic Würzburg and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
Stegner
David
D
Hagedorn
Ina
I
Kleinschnitz
Christoph
C
Braun
Attila
A
Kuijpers
Marijke E J
ME
Boesl
Michael
M
Chen
Qin
Q
Heemskerk
Johan W M
JW
Stoll
Guido
G
Frohman
Michael A
MA
Nieswandt
Bernhard
B
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
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010738:Type C Phospholipases; D010739:Phospholipase D; C106801:phospholipase D1