Academic Journal
HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases
| Title: | HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases |
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| 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 |
| ISSN: | 22132317 |
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| DOI: | 10.1016/j.redox.2017.05.019 |
| Published in: | Redox Biology |
| Language: | English |