cyclic-gmp and tangeretin

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.. 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.. 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.

Topics: Animals; Blood Platelets; Calcium Signaling; Cell Adhesion Molecules; Cyclic GMP; Dose-Response Relationship, Drug; Flavones; Hemostasis; Humans; Mice; Mice, Inbred C57BL; Microfilament Proteins; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Phosphoproteins; Phosphorylation; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Second Messenger Systems; Thrombosis; Time Factors

Flavonoids, compounds containing a 2-phenylbenzo(gamma)pyrane nucleus, are universally distributed among vascular plants. Even though flavonoids are ingested in a normal diet in average quantities of 1 g daily, their effects on the digestive system have only been recently investigated. This study used an in vitro model of colonic secretion, monolayers of T84 colonic adenocarcinoma cells mounted in Ussing chambers, to demonstrate that 100 mumol/L of either tangeritin or nobiletin, polymethoxylated flavonoids contained in citrus fruits, stimulated sustained electrogenic chloride secretion with a maximal short-circuit current of 3.3 microA/cm2. In contrast, naringin and hesperidin, glycosylated citrus flavonoids, stimulated minimal secretion, suggesting that carbohydrate substitutions inhibited their secretory potential. The secretion stimulated by tangeritin and nobiletin was synergistic with carbachol but not with vasoactive intestinal peptide and was inhibited by barium chloride, bumetanide, H-89, and Cl- depletion. These properties suggest that tangeritin and nobiletin stimulated Cl- secretion via the cAMP pathway; however, these flavonoids did not stimulate cAMP production to the extent seen with vasoactive intestinal peptide. These flavonoids did not autooxidize, suggesting that reactive oxygen species did not mediate this secretion. These observations suggest that dietary citrus flavonoids may modulate colonic secretion, possibly through direct interaction with intracellular secretory pathways.

Topics: Adenocarcinoma; Carbachol; Chlorides; Citrus; Colon; Colonic Neoplasms; Cyclic AMP; Cyclic GMP; Drug Synergism; Flavanones; Flavones; Flavonoids; Glycosylation; Humans; Kinetics; Tumor Cells, Cultured