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Open AccessArticle

Esculetin, a Coumarin Derivative, Prevents Thrombosis: Inhibitory Signaling on PLCγ2–PKC–AKT Activation in Human Platelets

1
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
2
Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
3
Department of Neurology, Chi Mei Medical Center, Tainan 710, Taiwan
4
Central Laboratory, Shin‐Kong Wu Ho‐Su Memorial Hospital, Taipei 111, Taiwan
5
Department of Chemistry, North Eastern Hill University, Shillong 793022, India
6
Department of Cardiovascular Center, Cathay General Hospital, Taipei 106, Taiwan
7
Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(11), 2731; https://doi.org/10.3390/ijms20112731
Received: 7 May 2019 / Revised: 27 May 2019 / Accepted: 31 May 2019 / Published: 3 June 2019
(This article belongs to the Special Issue Mechanisms and Therapeutics of Platelet Thrombus Formation)
Esculetin, a bioactive 6,7-dihydroxy derivative of coumarin, possesses pharmacological activities against obesity, diabetes, renal failure, and cardiovascular disorders (CVDs). Platelet activation plays a major role in CVDs. Thus, disrupting platelet activation represents an attractive therapeutic target. We examined the effect of esculetin in human platelet activation and experimental mouse models. At 10–80 μM, esculetin inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets. However, it had no effects on other agonists such as thrombin and U46619. Esculetin inhibited adenosine triphosphate release, P-selectin expression, hydroxyl radical (OH·) formation, Akt activation, and phospholipase C (PLC)γ2/protein kinase C (PKC) phosphorylation, but did not diminish mitogen-activated protein kinase phosphorylation in collagen-activated human platelets. Platelet function analysis indicated that esculetin substantially prolonged the closure time of whole blood. In experimental mice, esculetin significantly increased the occlusion time in thrombotic platelet plug formation and reduced mortality associated with acute pulmonary thromboembolism. However, it did not prolong the bleeding time. This study demonstrates that esculetin inhibits human platelet activation via hindering the PLCγ2–PKC cascade, hydroxyl radical formation, Akt activation, and ultimately suppressing platelet activation. Therefore, esculetin may act as an essential therapeutic agent for preventing thromboembolic diseases. View Full-Text
Keywords: arterial thrombosis; esculetin; experimental mice; human platelets; hydroxyl radical; signaling pathways arterial thrombosis; esculetin; experimental mice; human platelets; hydroxyl radical; signaling pathways
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MDPI and ACS Style

Hsia, C.-W.; Lin, K.-C.; Lee, T.-Y.; Hsia, C.-H.; Chou, D.-S.; Jayakumar, T.; Velusamy, M.; Chang, C.-C.; Sheu, J.-R. Esculetin, a Coumarin Derivative, Prevents Thrombosis: Inhibitory Signaling on PLCγ2–PKC–AKT Activation in Human Platelets. Int. J. Mol. Sci. 2019, 20, 2731.

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