http://atvb.ahajournals.org/content/early/2016/06/23/ATVBAHA.115.307105.abstract
- Patrick Münzer,
- Britta Walker-Allgaier,
- Sascha Geue,
- Eva Geuss,
- Gregor Hron,
- Dominik Rath,
- Daniela Eißler,
- Stefan Winter,
- Elke Schaeffeler,
- Monika Meinert,
- Martin Schaller,
- Andreas Greinacher,
- Matthias Schwab,
- Tobias Geisler,
- Christoph Kleinschnitz,
- Florian Lang,
- Meinrad Gawaz,
- Oliver Borst
+ Author Affiliations
- Correspondence to Oliver Borst, MD, Department of Cardiology and Cardiovascular Medicine, University of Tuebingen, Otfried Mueller-Str.10, 72076 Tuebingen, Germany. E-mail oliver.borst@med.uni-tuebingen.de; or Meinrad Gawaz, MD, Department of Cardiology and Cardiovascular Medicine, University of Tuebingen, Otfried Mueller-Str.10, 72076 Tuebingen, Germany. E-mail meinrad.gawaz@med.uni-tuebingen.de
Abstract
Objective—Activation of platelets by subendothelial collagen results in an increase of cytosolic Ca2+ concentration ([Ca2+]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 Ca2+ signaling and ischemic stroke in vivo.
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 [Ca2+]i in response to stimulation with collagen-related peptide or convulxin. The defective increase of [Ca2+]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.
Conclusions—PDK1 is required for Ca2+-dependent platelet activation on stimulation of collagen receptor glycoprotein VI, arterial thrombotic occlusion, and ischemic
stroke in vivo.
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