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PDK1 Determines Collagen-Dependent Platelet Ca2+ Signaling and Is Critical to Development of Ischemic Stroke In Vivo.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2016 Aug; Vol. 36 (8), pp. 1507-16. Date of Electronic Publication: 2016 Jun 23. - Publication Year :
- 2016
-
Abstract
- Objective: Activation of platelets by subendothelial collagen results in an increase of cytosolic Ca(2+) concentration ([Ca(2+)]i) and is followed by platelet activation and thrombus formation that may lead to vascular occlusion. The present study determined the role of phosphoinositide-dependent protein kinase 1 (PDK1) in collagen-dependent platelet Ca(2+) signaling and ischemic stroke in vivo.<br />Approach and Results: Platelet activation with collagen receptor glycoprotein VI agonists collagen-related peptide or convulxin resulted in a significant increase in PDK1 activity independent of second-wave signaling. PDK1 deficiency was associated with reduced platelet phospholipase Cγ2-dependent inositol-1,4,5-trisphosphate production and intracellular [Ca(2+)]i in response to stimulation with collagen-related peptide or convulxin. The defective increase of [Ca(2+)]i resulted in a substantial defect in activation-dependent platelet secretion and aggregation on collagen-related peptide stimulation. Furthermore, Rac1 activation and spreading, adhesion to collagen, and thrombus formation under high arterial shear rates were significantly diminished in PDK1-deficient platelets. Mice with PDK1-deficient platelets were protected against arterial thrombotic occlusion after FeCl3-induced mesenteric arterioles injury and ischemic stroke in vivo. These mice had significantly reduced brain infarct volumes, with a significantly increased survival of 7 days after transient middle cerebral artery occlusion without increase of intracerebral hemorrhage. Tail bleeding time was prolonged in pdk1(-/-) mice, reflecting an important role of PDK1 in primary hemostasis.<br />Conclusions: PDK1 is required for Ca(2+)-dependent platelet activation on stimulation of collagen receptor glycoprotein VI, arterial thrombotic occlusion, and ischemic stroke in vivo.<br /> (© 2016 American Heart Association, Inc.)
- Subjects :
- 3-Phosphoinositide-Dependent Protein Kinases deficiency
3-Phosphoinositide-Dependent Protein Kinases genetics
Animals
Disease Models, Animal
Genetic Predisposition to Disease
Infarction, Middle Cerebral Artery blood
Infarction, Middle Cerebral Artery pathology
Inositol 1,4,5-Trisphosphate blood
Mice, Knockout
Neuropeptides blood
Phenotype
Phospholipase C gamma blood
Platelet Adhesiveness
Platelet Aggregation
Platelet Membrane Glycoproteins deficiency
Platelet Membrane Glycoproteins genetics
Thrombosis blood
Thrombosis pathology
Time Factors
rac1 GTP-Binding Protein blood
3-Phosphoinositide-Dependent Protein Kinases metabolism
Blood Platelets enzymology
Calcium Signaling
Collagen metabolism
Infarction, Middle Cerebral Artery enzymology
Platelet Activation
Thrombosis enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 36
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 27339458
- Full Text :
- https://doi.org/10.1161/ATVBAHA.115.307105