Nature Medicine
11, 507 - 514 (2005)
Published online: 17 April 2005; | doi:10.1038/nm1232
PI 3-kinase p110 : a new target for antithrombotic therapyShaun P Jackson1, Simone M Schoenwaelder1, 5, Isaac Goncalves1, 5, Warwick S Nesbitt1, Cindy L Yap1, Christine E Wright2, Vijaya Kenche1, 4, Karen E Anderson1, Sacha M Dopheide1, Yuping Yuan1, Sharelle A Sturgeon2, 4, Hishani Prabaharan1, 4, Philip E Thompson1, 4, Gregg D Smith1, 4, Peter R Shepherd3, Nathalie Daniele3, Suhasini Kulkarni1, Belinda Abbott1, Dilek Saylik1, 4, Catherine Jones2, 4, Lucy Lu2, 4, Simon Giuliano1, Sascha C Hughan1, James A Angus2, Alan D Robertson4, 5
& Hatem H Salem1, 51
Australian Centre for Blood Diseases, Monash University, 6th Floor Burnet Building Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Prahran, Victoria, Australia 3181. 2
Department of Pharmacology, Level 8, Medical Building, Corner of Grattan Street and Royal Parade, University of Melbourne, Victoria, Australia 3010. 3
Department of Biochemistry and Molecular Biology, University College of London, Gower Street, London, WC1E6BT, UK. 4
Kinacia Pty Ltd, Cerylid Biosciences Ltd, 576 Swan Street, Richmond, Victoria, Australia 3121. 5
These authors contributed equally to this work. ADR and HHS are equal senior authors.
Correspondence should be addressed to Shaun P Jackson shaun.jackson@med.monash.edu.auPlatelet 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  IIb 3 (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110 isoform in regulating the formation and stability of integrin IIb3 adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110 inhibitors have been developed which prevent formation of stable integrin IIb3 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 p110 as an important new target for antithrombotic therapy.
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