Kinesin-1 Is a New Actor Involved in Platelet Secretion and Thrombus Stability

Arterioscler Thromb Vasc Biol. 2018 May;38(5):1037-1051. doi: 10.1161/ATVBAHA.117.310373. Epub 2018 Mar 8.

Abstract

Objective: Platelet secretion is crucial for many physiological platelet responses. Even though several regulators of the fusion machinery for secretory granule exocytosis have been identified in platelets, the underlying mechanisms are not yet fully characterized.

Approach and results: By studying a mouse model (cKO [conditional knockout]Kif5b) lacking Kif5b (kinesin-1 heavy chain) in its megakaryocytes and platelets, we evidenced unstable hemostasis characterized by an increase of blood loss associated to a marked tendency to rebleed in a tail-clip assay and thrombus instability in an in vivo thrombosis model. This instability was confirmed in vitro in a whole-blood perfusion assay under blood flow conditions. Aggregations induced by thrombin and collagen were also impaired in cKOKif5b platelets. Furthermore, P-selectin exposure, PF4 (platelet factor 4) secretion, and ATP release after thrombin stimulation were impaired in cKOKif5b platelets, highlighting the role of kinesin-1 in α-granule and dense granule secretion. Importantly, exogenous ADP rescued normal thrombin induced-aggregation in cKOKif5b platelets, which indicates that impaired aggregation was because of defective release of ADP and dense granules. Last, we demonstrated that kinesin-1 interacts with the molecular machinery comprising the granule-associated Rab27 (Ras-related protein Rab-27) protein and the Slp4 (synaptotagmin-like protein 4/SYTL4) adaptor protein.

Conclusions: Our results indicate that a kinesin-1-dependent process plays a role for platelet function by acting into the mechanism underlying α-granule and dense granule secretion.

Keywords: blood platelets; hemostasis; kinesin; platelet secretion.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Adenosine Triphosphate / blood
  • Animals
  • Blood Platelets / enzymology*
  • Blood Platelets / ultrastructure
  • Disease Models, Animal
  • Hemostasis*
  • Humans
  • Kinesin / blood
  • Kinesin / deficiency
  • Kinesin / genetics
  • Kinesin / metabolism*
  • Megakaryocytes / enzymology*
  • Megakaryocytes / ultrastructure
  • Mice, Inbred C57BL
  • Mice, Knockout
  • P-Selectin / blood
  • Platelet Activation*
  • Platelet Aggregation
  • Platelet Factor 4 / blood
  • Secretory Pathway
  • Secretory Vesicles / enzymology*
  • Secretory Vesicles / genetics
  • Secretory Vesicles / ultrastructure
  • Signal Transduction
  • Thrombosis / blood
  • Thrombosis / enzymology*
  • Thrombosis / genetics
  • Thrombosis / pathology
  • Vesicular Transport Proteins / blood
  • rab27 GTP-Binding Proteins / blood

Substances

  • KIF5B protein, human
  • P-Selectin
  • Sytl4 protein, mouse
  • Vesicular Transport Proteins
  • rab27 GTP-Binding Proteins
  • Platelet Factor 4
  • Adenosine Triphosphate
  • Kif5b protein, mouse
  • Kinesin