> Details

Münzer, Patrick; Walker-Allgaier, Britta; Geue, Sascha; Geuss, Eva; Hron, Gregor; Rath, Dominik; Eißler, Daniela; Winter, Stefan; Schaeffeler, Elke; Meinert, Monika; Schaller, Martin; Greinacher, Andreas; Schwab, Matthias; Geisler, Tobias; Kleinschnitz, Christoph; Lang, Florian; Gawaz, Meinrad; Borst, Oliver

PDK1 Determines Collagen-Dependent Platelet Ca 2+ Signaling and Is Critical to Development of Ischemic Stroke In Vivo

Reference
management

Bookmarks

Remove from
bookmarks

Share this on Whatsapp

Close

Bookmarks



You can manage bookmarks using lists, please log in to your user account for this.
  • Media type: E-Article
  • Title: PDK1 Determines Collagen-Dependent Platelet Ca 2+ Signaling and Is Critical to Development of Ischemic Stroke In Vivo
  • Contributor: Münzer, Patrick; Walker-Allgaier, Britta; Geue, Sascha; Geuss, Eva; Hron, Gregor; Rath, Dominik; Eißler, Daniela; Winter, Stefan; Schaeffeler, Elke; Meinert, Monika; Schaller, Martin; Greinacher, Andreas; Schwab, Matthias; Geisler, Tobias; Kleinschnitz, Christoph; Lang, Florian; Gawaz, Meinrad; Borst, Oliver
  • imprint: Ovid Technologies (Wolters Kluwer Health), 2016
  • Published in: Arteriosclerosis, Thrombosis, and Vascular Biology
  • Language: English
  • DOI: 10.1161/atvbaha.115.307105
  • ISSN: 1079-5642; 1524-4636
  • Keywords: Cardiology and Cardiovascular Medicine
  • Origination:
  • Footnote:
  • Description: <jats:sec> <jats:title>Objective—</jats:title> <jats:p> Activation of platelets by subendothelial collagen results in an increase of cytosolic Ca <jats:sup>2+</jats:sup> concentration ([Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> ) 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 <jats:sup>2+</jats:sup> signaling and ischemic stroke in vivo. </jats:p> </jats:sec> <jats:sec> <jats:title>Approach and Results—</jats:title> <jats:p> 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 <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> in response to stimulation with collagen-related peptide or convulxin. The defective increase of [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> 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 FeCl <jats:sub>3</jats:sub> -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 <jats:italic>pdk1</jats:italic> <jats:sup>−/−</jats:sup> mice, reflecting an important role of PDK1 in primary hemostasis. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p> PDK1 is required for Ca <jats:sup>2+</jats:sup> -dependent platelet activation on stimulation of collagen receptor glycoprotein VI, arterial thrombotic occlusion, and ischemic stroke in vivo. </jats:p> </jats:sec>