Esculetin, A coumarin derivative, prevents thrombosis: Inhibitory signaling on PLCγ2-PKC-AKT activation in human platelets

Chih Wei Hsia, Kao Chang Lin, Tzu Yin Lee, Chih Hsuan Hsia, Duen Suey Chou, Thanasekaran Jayakumar, Marappan Velusamy, Joen Rong Sheu

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number2731
JournalInternational Journal of Molecular Sciences
Volume20
Issue number11
DOIs
Publication statusPublished - Jun 1 2019

Keywords

  • Arterial thrombosis
  • Esculetin
  • Experimental mice
  • Human platelets
  • Hydroxyl radical
  • Signaling pathways

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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