PI 3-kinase p110beta: a new target for antithrombotic therapy.
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.
Jackson
Shaun P
SP
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
Schoenwaelder
Simone M
SM
Goncalves
Isaac
I
Nesbitt
Warwick S
WS
Yap
Cindy L
CL
Wright
Christine E
CE
Kenche
Vijaya
V
Anderson
Karen E
KE
Dopheide
Sacha M
SM
Yuan
Yuping
Y
Sturgeon
Sharelle A
SA
Prabaharan
Hishani
H
Thompson
Philip E
PE
Smith
Gregg D
GD
Shepherd
Peter R
PR
Daniele
Nathalie
N
Kulkarni
Suhasini
S
Abbott
Belinda
B
Saylik
Dilek
D
Jones
Catherine
C
Lu
Lucy
L
Giuliano
Simon
S
Hughan
Sascha C
SC
Angus
James A
JA
Robertson
Alan D
AD
Salem
Hatem H
HH
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
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