title: PI 3-kinase p110beta: a new target for antithrombotic therapy.
abstract: Platelet activation at sites of vascular injury is essential for the arrest of bleeding; however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances (high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(3) adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K p110beta as an important new target for antithrombotic therapy.
authors.affiliation: Australian Centre for Blood Diseases, Monash University, 6th Floor Burnet Building Alfred Medical Research and Education Precinct, Prahran, Victoria, Australia 3181. shaun.jackson@med.monash.edu.au
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
authors.forename: Simone M
authors.initials: SM
authors.lastname: Schoenwaelder
authors.forename: Isaac
authors.initials: I
authors.lastname: Goncalves
authors.forename: Warwick S
authors.initials: WS
authors.lastname: Nesbitt
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Yap
authors.forename: Christine E
authors.initials: CE
authors.lastname: Wright
authors.forename: Vijaya
authors.initials: V
authors.lastname: Kenche
authors.forename: Karen E
authors.initials: KE
authors.lastname: Anderson
authors.forename: Sacha M
authors.initials: SM
authors.lastname: Dopheide
authors.forename: Yuping
authors.initials: Y
authors.lastname: Yuan
authors.forename: Sharelle A
authors.initials: SA
authors.lastname: Sturgeon
authors.forename: Hishani
authors.initials: H
authors.lastname: Prabaharan
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thompson
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Smith
authors.forename: Peter R
authors.initials: PR
authors.lastname: Shepherd
authors.forename: Nathalie
authors.initials: N
authors.lastname: Daniele
authors.forename: Suhasini
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Belinda
authors.initials: B
authors.lastname: Abbott
authors.forename: Dilek
authors.initials: D
authors.lastname: Saylik
authors.forename: Catherine
authors.initials: C
authors.lastname: Jones
authors.forename: Lucy
authors.initials: L
authors.lastname: Lu
authors.forename: Simon
authors.initials: S
authors.lastname: Giuliano
authors.forename: Sascha C
authors.initials: SC
authors.lastname: Hughan
authors.forename: James A
authors.initials: JA
authors.lastname: Angus
authors.forename: Alan D
authors.initials: AD
authors.lastname: Robertson
authors.forename: Hatem H
authors.initials: HH
authors.lastname: Salem
mesh_terms: D000818:Animals; D001158:Arteries / Q000473:pathology*; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism; D005434:Flow Cytometry; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010973:Platelet Adhesiveness / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D012212:Rheology; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology; D020668:rap GTP-Binding Proteins / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D012701:Serotonin; D020668:rap GTP-Binding Proteins; C492136:Rap1b protein, mouse