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

Redox Biology

Ying-Ting Lin¹  Jia-Hau Lee¹  I-Hua Chen²  Chin-Chung Wu²  Po-Hsiung Kung²  Pei-Wen Hsieh³ 

[1] Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan;Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan;Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan;

关键词: HPW-RX40;    Nitrostyrene;    Protein disulfide isomerase;    Platelets;    Anti-thrombotic agents;   

DOI  :  10.1016/j.redox.2017.05.019

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown