HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases
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 ma...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-10-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323171730246X |
| _version_ | 1818853246830116864 |
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| author | Po-Hsiung Kung Pei-Wen Hsieh Ying-Ting Lin Jia-Hau Lee I-Hua Chen Chin-Chung Wu |
| author_facet | Po-Hsiung Kung Pei-Wen Hsieh Ying-Ting Lin Jia-Hau Lee I-Hua Chen Chin-Chung Wu |
| author_sort | Po-Hsiung Kung |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T07:33:46Z |
| format | Article |
| id | doaj.art-b621ed25cc484c1db26b37bbc93a252f |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-19T07:33:46Z |
| publishDate | 2017-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-b621ed25cc484c1db26b37bbc93a252f2022-12-21T20:30:37ZengElsevierRedox Biology2213-23172017-10-0113C26627710.1016/j.redox.2017.05.019HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerasesPo-Hsiung Kung0Pei-Wen Hsieh1Ying-Ting Lin2Jia-Hau Lee3I-Hua Chen4Chin-Chung Wu5Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, TaiwanGraduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, TaiwanDepartment of Biotechnology, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Biotechnology, Kaohsiung Medical University, Kaohsiung, TaiwanGraduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, TaiwanGraduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, TaiwanProtein 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.http://www.sciencedirect.com/science/article/pii/S221323171730246XHPW-RX40NitrostyreneProtein disulfide isomerasePlateletsAnti-thrombotic agents |
| spellingShingle | Po-Hsiung Kung Pei-Wen Hsieh Ying-Ting Lin Jia-Hau Lee I-Hua Chen Chin-Chung Wu HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases Redox Biology HPW-RX40 Nitrostyrene Protein disulfide isomerase Platelets Anti-thrombotic agents |
| title | HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases |
| title_full | HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases |
| title_fullStr | HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases |
| title_full_unstemmed | HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases |
| title_short | HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases |
| title_sort | hpw rx40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases |
| topic | HPW-RX40 Nitrostyrene Protein disulfide isomerase Platelets Anti-thrombotic agents |
| url | http://www.sciencedirect.com/science/article/pii/S221323171730246X |
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