Platelet PI3Kβ and GSK3 regulate thrombus stability at a high shear rate.
Class IA phosphoinositide 3-kinase β (PI3Kβ) is considered a potential drug target in arterial thrombosis, which is a major cause of death worldwide. Here we show that a striking phenotype of mice with selective p110β deletion in the megakaryocyte lineage is thrombus instability at a high shear rate, which is an effect that is not detected in the absence of p110α in platelets. The high shear rate-dependent thrombus instability in the absence of p110β is observed both ex vivo and in vivo with the formation of platelet emboli. Moreover, PI3Kβ is required for the recruitment of new platelets to a growing thrombus when a pathological high shear is applied. Treatment of human blood with AZD6482, a selective PI3Kβ inhibitor, phenocopies p110β deletion in mouse platelets, which highlights the role of the kinase activity of p110β. Within the growing platelet thrombus, p110β inactivation impairs the activating phosphorylations of Akt and the inhibitory phosphorylation of GSK3. In accord with these data, pharmacologic inhibition of GSK3 restores thrombus stability. Thus, platelet PI3Kβ is not essential for thrombus growth and stability at normal arterial shear but has a specific and critical role in maintaining the integrity of the formed thrombus on elevation of shear rate, suggesting a potential risk of embolization on treatment with PI3Kβ inhibitors.
INSERM, U1048 and Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, Centre Hospitalier Universitaire-Rangueil, Toulouse, France;
Pierre-Alexandre
PA
Laurent
INSERM, U1048 and Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, Centre Hospitalier Universitaire-Rangueil, Toulouse, France;
Sonia
S
Séverin
Unité Mixte de Recherche-S949 INSERM-Université de Strasbourg, Établissement Français du Sang-Alsace, Strasbourg Cedex, France;
Béatrice
B
Hechler
Cell Signalling, University College London Cancer Institute, Paul O'Gorman Building, University College London, London, United Kingdom; and.
Bart
B
Vanhaesebroeck
INSERM, U1048 and Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, Centre Hospitalier Universitaire-Rangueil, Toulouse, France; Centre Hospitalier Universitaire de Toulouse, Laboratoire d'Hématologie, Toulouse Cedex, France.
Bernard
B
Payrastre
INSERM, U1048 and Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, Centre Hospitalier Universitaire-Rangueil, Toulouse, France;
Marie-Pierre
MP
Gratacap
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D040542:Mechanotransduction, Cellular; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D013314:Stress, Mechanical; D013927:Thrombosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D062367:ortho-Aminobenzoates / Q000494:pharmacology
C578518:2-(1-(7-methyl-2-morpholin-4-yl-4-oxo-4H-pyrido(1,2-a)pyrimidin-9-yl)ethylamino)benzoic acid; C473711:Chir 99021; D011725:Pyridines; D011743:Pyrimidines; D011744:Pyrimidinones; D062367:ortho-Aminobenzoates; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3