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2017 ; 13
(ä): 266-277
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HPW-RX40 prevents human platelet activation by attenuating cell surface protein
disulfide isomerases
#MMPMID28600983
Kung PH
; Hsieh PW
; Lin YT
; Lee JH
; Chen IH
; Wu CC
Redox Biol
2017[Oct]; 13
(ä): 266-277
PMID28600983
show ga
Protein disulfide isomerase (PDI) present at platelet surfaces has been
considered to play an important role in the conformational change and activation
of the integrin glycoprotein IIb/IIIa (GPIIb/IIIa) and thus enhances platelet
aggregation. Growing evidences indicated that platelet surface PDI may serve as a
potential target for developing of a new class of antithrombotic agents. In the
present study, we investigated the effects of HPW-RX40, a chemical derivative of
?-nitrostyrene, on platelet activation and PDI activity. HPW-RX40 inhibited
platelet aggregation, GPIIb/IIIa activation, and P-selectin expression in human
platelets. Moreover, HPW-RX40 reduced thrombus formation in human whole blood
under flow conditions, and protects mice from FeCl(3)-induced carotid artery
occlusion. HPW-RX40 inhibited the activity of recombinant PDI family proteins
(PDI, ERp57, and ERp5) as well as suppressed cell surface PDI activity of
platelets in a reversible manner. Exogenous addition of PDI attenuated the
inhibitory effect of HPW-RX40 on GPIIb/IIIa activation. Structure-based molecular
docking simulations indicated that HPW-RX40 binds to the active site of PDI by
forming hydrogen bonds. In addition, HPW-RX40 neither affected the cell viability
nor induced endoplasmic reticulum stress in human cancer A549 and MDA-MB-231
cells. Taken together, our results suggest that HPW-RX40 is a reversible and
non-cytotoxic PDI inhibitor with antiplatelet effects, and it may have a
potential for development of novel antithrombotic agents.