title: Antithrombotic activities of ferulic acid via intracellular cyclic nucleotide signaling.
abstract: Ferulic acid (FA) produces protective effects against cardiovascular dysfunctions. However, the mechanisms of FA is still not known. Here we examined the antithrombotic effects of FA and its potential mechanisms. Anticoagulation assays and platelet aggregation was evaluated in vitro and in vivo. Thromboxane B2 (TXB2), cyclic adenosine monophosphate(cAMP), and cyclic guanosine monophosphate (cGMP) was determined using enzyme immunoassay kits. Nitric oxide (NO) production was measured using the Griess reaction. Protein expression was detected by Western blotting analysis. Oral administration of FA prevented death caused by pulmonary thrombosis and prolonged the tail bleeding and clotting time in mice,while, it did not alter the coagulation parameters, including the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). In addition, FA (50-200 µM) dose-dependently inhibited platelet aggregation induced by various platelet agonists, including adenosine diphosphate (ADP), thrombin, collagen, arachidonic acid (AA), and U46619. Further, FA attenuated intracellular Ca(2)(+) mobilization and TXB2 production induced by the platelet agonists. FA increased the levels of cAMP and cGMP and phosphorylated vasodilator-stimulated phosphoprotein (VASP) while decreased phospho-MAPK (mitogen-activated protein kinase) and phosphodiesterase (PDE) in washed rat platelets, VASP is a substrate of cyclic nucleotide and PDE is an enzyme family responsible for hydrolysis of cAMP/cGMP. These results suggest that antithrombotic activities of FA may be regulated by inhibition of platelet aggregation, rather than through inhibiting the release of thromboplastin or formation of thrombin. The mechanism of this action may involve activation of cAMP and cGMP signaling.
authors.affiliation: Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, PR China; No. 97 Hospital of CPLA, 226 Tongshan Road, Xuzhou 221000, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Hong
authors.affiliation: Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, PR China.
authors.forename: Zeng-Chun
authors.initials: ZC
authors.lastname: Ma
authors.affiliation: Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.affiliation: Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, PR China.
authors.forename: Yu-Guang
authors.initials: YG
authors.lastname: Wang
authors.affiliation: Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, PR China.
authors.forename: Hong-Ling
authors.initials: HL
authors.lastname: Tan
authors.affiliation: Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, PR China.
authors.forename: Cheng-Rong
authors.initials: CR
authors.lastname: Xiao
authors.affiliation: Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, PR China.
authors.forename: Qian-De
authors.initials: QD
authors.lastname: Liang
authors.affiliation: Departments of Behavioral Medicine & Psychiatry and Physiology & Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA. Electronic address: hzhang@hsc.wvu.edu.
authors.forename: Han-Ting
authors.initials: HT
authors.lastname: Zhang
authors.affiliation: Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, PR China. Electronic address: gaoyue@bmi.ac.cn.
authors.forename: Yue
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003373:Coumaric Acids / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006470:Hemorrhage / Q000150:complications; D042541:Intracellular Space / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D013927:Thrombosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013929:Thromboxane B2 / Q000096:biosynthesis; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D003373:Coumaric Acids; D005343:Fibrinolytic Agents; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D013481:Superoxides; D009569:Nitric Oxide; D013929:Thromboxane B2; C004999:ferulic acid; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP; D002118:Calcium
keywords: Antiplatelet; Antithrombotic; Coagulation; Ferulic acid