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HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases

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Title: HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases
Authors: Po-Hsiung Kung, Pei-Wen Hsieh, Ying-Ting Lin, Jia-Hau Lee, I-Hua Chen, Chin-Chung Wu
Source: Redox Biology, Vol 13, Iss C, Pp 266-277 (2017)
Publisher Information: Elsevier, 2017.
Publication Year: 2017
Collection: LCC:Medicine (General)
LCC:Biology (General)
Subject Terms: HPW-RX40, Nitrostyrene, Protein disulfide isomerase, Platelets, Anti-thrombotic agents, Medicine (General), R5-920, Biology (General), QH301-705.5
More Details: 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 β-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 FeCl3-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.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2213-2317
Relation: http://www.sciencedirect.com/science/article/pii/S221323171730246X; https://doaj.org/toc/2213-2317
DOI: 10.1016/j.redox.2017.05.019
Access URL: https://doaj.org/article/b621ed25cc484c1db26b37bbc93a252f
Accession Number: edsdoj.b621ed25cc484c1db26b37bbc93a252f
Database: Directory of Open Access Journals
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  Data: HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases
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  Data: Redox Biology, Vol 13, Iss C, Pp 266-277 (2017)
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  Data: 2017
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  Data: <searchLink fieldCode="DE" term="%22HPW-RX40%22">HPW-RX40</searchLink><br /><searchLink fieldCode="DE" term="%22Nitrostyrene%22">Nitrostyrene</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+disulfide+isomerase%22">Protein disulfide isomerase</searchLink><br /><searchLink fieldCode="DE" term="%22Platelets%22">Platelets</searchLink><br /><searchLink fieldCode="DE" term="%22Anti-thrombotic+agents%22">Anti-thrombotic agents</searchLink><br /><searchLink fieldCode="DE" term="%22Medicine+%28General%29%22">Medicine (General)</searchLink><br /><searchLink fieldCode="DE" term="%22R5-920%22">R5-920</searchLink><br /><searchLink fieldCode="DE" term="%22Biology+%28General%29%22">Biology (General)</searchLink><br /><searchLink fieldCode="DE" term="%22QH301-705%2E5%22">QH301-705.5</searchLink>
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  Label: Description
  Group: Ab
  Data: 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 β-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 FeCl3-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.
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