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Resistance to thromboembolism in PI3Kγ‐deficient mice
Author(s) -
Hirsch Emilio,
Bosco Ornella,
Tropel Philippe,
Laffargue Muriel,
Calvez Ronan,
Altruda Fiorella,
Wymann Matthias P.,
Montrucchio Giuseppe
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.00-0810fje
Subject(s) - platelet , thrombus , protein kinase b , thrombin , platelet activation , thrombosis , phosphorylation , antithrombotic , medicine , chemistry , receptor , endocrinology , biochemistry
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 PI3Kγ isoform were stimulated with ADP, aggregation was impaired. Collagen or thrombin, however, evoked a normal response. ADP stimulation of PI3Kγ‐deficient platelets resulted in decreased PKB/Akt phosphorylation and α IIb β 3 fibrinogen receptor activation. These effects did not influence bleeding time but protected PI3Kγ‐null mice from death caused by ADP‐induced platelet‐dependent thromboembolic vascular occlusion. This result demonstrates an unsuspected, well‐defined role for PI3Kγ downstream of ADP and suggests that pharmacological targeting of PI3Kγ has a potential use as antithrombotic therapy.