title: Histone deacetylase inhibitors reduce glycoprotein VI expression and platelet responses to collagen related peptide.
abstract: BACKGROUND
  Platelet Glycoprotein (GP)VI is a member of the immunoglobulin superfamily expressed only on platelets, and is the major signalling receptor for collagen. Histone deacetylase inhibitors (HDACi) are anti-cancer agents used for the treatment of haematological malignancies, and we examined the effects of administration of HDACi to mice on platelet function including responses to agonists including collagen related peptide (CRP).
  
  
  METHODS
  C57BL/6 mice were injected with two structurally different HDACi, panobinostat and romidepsin, for three days and platelet receptor levels and responses to agonists were assessed by flow cytometry and western blot.
  
  
  RESULTS
  Platelets from mice treated with either HDACi were impaired in their ability to respond to CRP, but not thrombin or adenosine diphosphate (ADP). HDACi treatment increased acetylation of megakaryocytic GPVI, resulting in loss of intact (~60-65-kDa) GPVI and formation of ~10-kDa remnant GPVI. Circulating platelets had reduced surface and total expression of GPVI. Platelets from mice treated with HDACi had impaired GPVI signalling following treatment with CRP, resulting in inhibition of Syk phosphorylation and activation, and the final common pathways of platelet activation.
  
  
  CONCLUSIONS
  Administration of HDACi in vivo may ablate platelet responses to agonists and platelet function.
authors: Cancer Research Division, The Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne 3002, Victoria, Australia.
authors: Mark J
authors: MJ
authors: Bishton
authors: Elizabeth E
authors: EE
authors: Gardiner
authors: Simon J
authors: SJ
authors: Harrison
authors: H Miles
authors: HM
authors: Prince
authors: Ricky W
authors: RW
authors: Johnstone
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D047630:Depsipeptides / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000077767:Panobinostat; D010455:Peptides / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D010455:Peptides; D010980:Platelet Membrane Glycoproteins; C435908:collagen-related peptide; C098341:platelet membrane glycoprotein VI; D000077767:Panobinostat; C087123:romidepsin