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Open AccessArticle

Suppression of Human Platelet Activation via Integrin αIIbβ3 Outside-In Independent Signal and Reduction of the Mortality in Pulmonary Thrombosis by Auraptene

1
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
2
Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan
3
Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
4
Department of Medical Research, Taipei Medical University Hospital, Taipei 110, Taiwan
5
Department of Chemistry, North Eastern Hill University, Shillong 793022, India
6
Department of Cardiovascular Surgery, Mackay Memorial Hospital, Taipei 104, Taiwan
7
Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(22), 5585; https://doi.org/10.3390/ijms20225585
Received: 23 September 2019 / Revised: 6 November 2019 / Accepted: 7 November 2019 / Published: 8 November 2019
(This article belongs to the Special Issue Mechanisms and Therapeutics of Platelet Thrombus Formation)
Auraptene is the most abundant coumarin derivative from plants. The pharmacological value of this compound has been well demonstrated, especially in the prevention of cancer and neurodegenerative diseases. Platelet activation is a major factor contributing to arterial thrombosis. Thus, this study evaluated the influence of auraptene in platelet aggregation and thrombotic formation. Auraptene inhibited platelet aggregation in human platelets stimulated with collagen only. However, auraptene was not effective in inhibiting platelet aggregation stimulated with thrombin, arachidonic acid, and U46619. Auraptene also repressed ATP release, [Ca2+]i mobilization, and P-selectin expression. Moreover, it markedly blocked PAC-1 binding to integrin αIIbβ3. However, it had no influence on properties related to integrin αIIbβ3-mediated outside-in signaling, such as the adhesion number, spreading area of platelets, and fibrin clot retraction. Auraptene inhibited the phosphorylation of Lyn-Fyn-Syk, phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), Akt, and mitogen-activated protein kinases (MAPKs; extracellular-signal-regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK1/2), but not p38 MAPK). Neither SQ22536, an adenylate cyclase inhibitor, nor ODQ, a guanylate cyclase inhibitor, reversed the auraptene-mediated inhibition of platelet aggregation. Auraptene reduced mortality caused by adenosine diphosphate (ADP)-induced pulmonary thromboembolism. In conclusion, this study provides definite evidence that auraptene signifies a potential therapeutic agent for preventing thromboembolic disorders. View Full-Text
Keywords: auraptene; human platelet; arterial thrombosis; ERK1/2/JNK1/2; experimental mice auraptene; human platelet; arterial thrombosis; ERK1/2/JNK1/2; experimental mice
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Hsia, C.-W.; Tsai, C.-L.; Sheu, J.-R.; Lu, W.-J.; Hsia, C.-H.; Velusamy, M.; Jayakumar, T.; Li, J.-Y. Suppression of Human Platelet Activation via Integrin αIIbβ3 Outside-In Independent Signal and Reduction of the Mortality in Pulmonary Thrombosis by Auraptene. Int. J. Mol. Sci. 2019, 20, 5585.

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