Impaired platelet responses to thrombin and collagen in AKT-1-deficient mice.
We investigated the role of Akt-1, one of the major downstream effectors of phosphoinositide 3-kinase (PI3K), in platelet function using mice in which the gene for Akt-1 had been inactivated. Using ex vivo techniques, we showed that Akt-1-deficient mice exhibited impaired platelet aggregation and spreading in response to various agonists. These differences were most apparent in platelets activated with low concentrations of thrombin. Although Akt-1 is not the predominant Akt isoform in mouse platelets, its absence diminished the amount of total phospho-Akt and inhibited increases in intracellular Ca(2+) concentration in response to thrombin. Moreover, thrombin-induced platelet alpha-granule release as well as release of adenosine triphosphate from dense granules was also defective in Akt-1-null platelets. Although the absence of Akt-1 did not influence expression of the major platelet receptors for thrombin and collagen, fibrinogen binding in response to these agonists was significantly reduced. As a consequence of impaired alpha(IIb)beta(3) activation and platelet aggregation, Akt-1 null mice showed significantly longer bleeding times than wild-type mice.
Chen
Juhua
J
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic Foundation, NB50, 9500 Euclid Ave, Cleveland, OH 44195, USA.
De
Sarmishtha
S
Damron
Derek S
DS
Chen
William S
WS
Hay
Nissim
N
Byzova
Tatiana V
TV
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology*; D005340:Fibrinogen / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010766:Phosphorylation; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D013917:Thrombin / Q000494:pharmacology*
D039661:Integrin beta3; D019007:P-Selectin; D011518:Proto-Oncogene Proteins; D015240:Phorbol 12,13-Dibutyrate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005340:Fibrinogen; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D013917:Thrombin; D002118:Calcium