Resistance to thromboembolism in PI3Kgamma-deficient mice.
Platelet aggregation and subsequent thrombosis are the major cause of ischemic diseases such as heart attack and stroke. ADP, acting via G protein-coupled receptors (GPCRs), is an important signal in thrombus formation and involves activation of phosphoinositide 3-kinases (PI3K). When platelets from mice lacking the G protein-activated PI3Kgamma isoform were stimulated with ADP, aggregation was impaired. Collagen or thrombin, however, evoked a normal response. ADP stimulation of PI3Kgamma-deficient platelets resulted in decreased PKB/Akt phosphorylation and alpha(IIb)beta(3) fibrinogen receptor activation. These effects did not influence bleeding time but protected PI3Kgamma-null mice from death caused by ADP-induced platelet-dependent thromboembolic vascular occlusion. This result demonstrates an unsuspected, well-defined role for PI3Kgamma downstream of ADP and suggests that pharmacological targeting of PI3Kgamma has a potential use as antithrombotic therapy.
Hirsch
E
E
Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Via Santina 5 bis, 10126 Turin, Italy. emilio.hirsch@unito.it
Bosco
O
O
Tropel
P
P
Laffargue
M
M
Calvez
R
R
Altruda
F
F
Wymann
M
M
Montrucchio
G
G
D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism; D058544:Class Ib Phosphatidylinositol 3-Kinase; D005340:Fibrinogen / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D010974:Platelet Aggregation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface / Q000378:metabolism; D013923:Thromboembolism / Q000378:metabolism*
D000244:Adenosine Diphosphate; D058544:Class Ib Phosphatidylinositol 3-Kinase; D005340:Fibrinogen; D019204:GTP-Binding Proteins; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface; C546764:Pik3cg protein, mouse