Histone deacetylase inhibitors reduce glycoprotein VI expression and platelet responses to collagen related peptide.

Abstract

INTRODUCTION:

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).

MATERIALS AND 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: Mark J Bishton, Elizabeth E Gardiner, Simon J Harrison, H Miles Prince, Ricky W Johnstone
• Journal: Thrombosis research (Thromb Res) Vol. 131 Issue 6 Pg. 514-20 (Jun 2013) ISSN: 1879-2472 [Electronic] United States
• PMID: 23642854 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Carrier Proteins
• Depsipeptides
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Indoles
• Peptides
• Platelet Membrane Glycoproteins
• collagen-related peptide
• platelet membrane glycoprotein VI
• Panobinostat
• romidepsin

Topics

• Acetylation (drug effects)
• Animals
• Blood Platelets (drug effects, metabolism)
• Carrier Proteins (metabolism)
• Cells, Cultured
• Depsipeptides (pharmacology)
• Down-Regulation (drug effects)
• Histone Deacetylase Inhibitors (pharmacology)
• Hydroxamic Acids (pharmacology)
• Indoles (pharmacology)
• Megakaryocytes (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Panobinostat
• Peptides (metabolism)
• Platelet Aggregation (drug effects)
• Platelet Membrane Glycoproteins (genetics)
• Signal Transduction (drug effects)