title: Tangeretin regulates platelet function through inhibition of phosphoinositide 3-kinase and cyclic nucleotide signaling.
abstract: OBJECTIVE
  Dietary flavonoids have long been appreciated in reducing cardiovascular disease risk factors, but their mechanisms of action are complex in nature. In this study, the effects of tangeretin, a dietary flavonoid, were explored on platelet function, signaling, and hemostasis.
  
  
  RESULTS
  Tangeretin inhibited agonist-induced human platelet activation in a concentration-dependent manner. It inhibited agonist-induced integrin αIIbβ3 inside-out and outside-in signaling, intracellular calcium mobilization, and granule secretion. Tangeretin also inhibited human platelet adhesion and subsequent thrombus formation on collagen-coated surfaces under arterial flow conditions in vitro and reduced hemostasis in mice. Further characterization to explore the mechanism by which tangeretin inhibits platelet function revealed distinctive effects of platelet signaling. Tangeretin was found to inhibit phosphoinositide 3-kinase-mediated signaling and increase cGMP levels in platelets, although phosphodiesterase activity was unaffected. Consistent with increased cGMP levels, tangeretin increased the phosphorylation of vasodilator-stimulated phosphoprotein at S239.
  
  
  CONCLUSIONS
  This study provides support for the ability and mechanisms of action of dietary flavonoids to modulate platelet signaling and function, which may affect the risk of thrombotic disease.
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Vaiyapuri
authors.forename: Marfoua S
authors.initials: MS
authors.lastname: Ali
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Moraes
authors.forename: Tanya
authors.initials: T
authors.lastname: Sage
authors.forename: Kirsty R
authors.initials: KR
authors.lastname: Lewis
authors.forename: Chris I
authors.initials: CI
authors.lastname: Jones
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gibbins
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D020013:Calcium Signaling / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000097:blood; D058539:Phosphatidylinositol 3-Kinase / Q000097:blood; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000097:blood; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects*; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000097:blood; D015290:Second Messenger Systems / Q000187:drug effects*; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*; D013997:Time Factors; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D047309:Flavones; D008840:Microfilament Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D047428:Protein Kinase Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D006152:Cyclic GMP; C059006:tangeretin
keywords: blood platelets; cAMP; cGMP; tangeretin; thrombosis