Myricetin as a promising inhibitor of platelet fibrinogen receptor in humans
Yi Chang,
Chih-Wei Hsia,
Wei-Chieh Huang,
Thanasekaran Jayakumar,
Chih-Hsuan Hsia,
Ting-Lin Yen,
Joen-Rong Sheu,
Shaw-Min Hou
Affiliations
Yi Chang
Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 242, Taiwan
Chih-Wei Hsia
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
Wei-Chieh Huang
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
Thanasekaran Jayakumar
Department of Ecology and Environmental Sciences, Pondicherry University, Puducherry, 605014, India
Chih-Hsuan Hsia
Translational Medicine Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan
Ting-Lin Yen
Department of Medical Research, Cathay General Hospital, Taipei, 106, Taiwan
Joen-Rong Sheu
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; Corresponding author. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei, 11031, Taiwan.
Shaw-Min Hou
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 242, Taiwan; Department of Cardiovascular Center, Cathay General Hospital, Taipei, 106, Taiwan; Corresponding author. Department of Cardiovascular Center, Cathay General Hospital, 280 Sec. 4, Jen-Ai Rd., Taipei, 106, Taiwan.
Platelets play a vital role in the formation of dangerous arterial thrombosis. Platelets are activated by adhesive proteins or soluble agonists through their specific receptors. The receptor-mediated signaling pathways lead to common signaling events, which result in shape changes and inside–out signaling, leading fibrinogen binding to glycoprotein IIb/IIIa complex (integrin αIIbβ3). This interaction initiates integrin αIIbβ3-mediated outside-in signaling, subsequently culminating in granule secretion and aggregation. Myricetin is a flavonoid that occurs in a variety of plants. Although myricetin has been demonstrated to have several bioactive properties, its role in platelet activation has not been extensively studied. The present study demonstrated the ability of myricetin to inhibit platelet aggregation stimulated by collagen, thrombin, and U46619. Myricetin reduced the ATP-release, cytosolic Ca2+ mobilization, and P-selectin expression and the activation of PLCγ2/PKC, PI3K/Akt/GSK3β, and MAPK. Myricetin exerted a direct inhibitory effect on the activation of integrin αIIbβ3 by disrupting the binding between FITC-PAC-1 and the integrin. Moreover, myricetin suppressed integrin αIIbβ3-mediated outside–in signaling, such as integrin β3, Src, and Syk phosphorylation on immobilized fibrinogen. In animal studies, myricetin significantly prolonged the occlusion time of thrombotic platelet plug formation in mesenteric microvessels without extending bleeding time. This study concludes that myricetin is a natural integrin αIIbβ3 inhibitor and a novel antithrombotic agent.
