AUTHOR=Kim Tae In , Kim Yeon-Ji , Kim Kyungho 

TITLE=Extract of Seaweed Codium fragile Inhibits Integrin αIIbβ3-Induced Outside-in Signaling and Arterial Thrombosis

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.685948

DOI=10.3389/fphar.2021.685948

ISSN=1663-9812

ABSTRACT=<p>Seaweeds are thought to be promising candidates for functional foods and to help prevent thrombotic and related cardiovascular diseases. <italic>Codium fragile</italic> (Suringer) Hariot has been traditionally used as a culinary ingredient, and it possesses a range of biological activities, including the inhibition of platelet function. However, the mechanism of this inhibition is unclear. The aim of this study was to examine the inhibitory effect of <italic>C. fragile</italic> in platelet function. The antiplatelet activity of <italic>C. fragile</italic> on agonist-activated platelet aggregation, granule secretion, calcium mobilization, platelet spreading, and clot retraction was assessed. The phosphorylation of c-Src, Syk, PLCγ2, and several proteins involving in the αIIbβ3 integrin outside-in signaling pathway were also studied in thrombin and CRP-stimulated platelets. The antithrombotic effect was investigated in mice using ferric chloride-induced arterial thrombus formation <italic>in vivo</italic>. Transection tail bleeding time was used to evaluate whether <italic>C. fragile</italic> inhibited primary hemostasis. The main components and contents of <italic>C. fragile</italic> ethanol extract were confirmed by GC-MS analysis. <italic>C. fragile</italic> significantly impaired agonist-induced platelet aggregation granule secretion, calcium mobilization, platelet spreading, and clot retraction. Biochemical analysis revealed that <italic>C. fragile</italic> inhibited the agonist-induced activation of c-Src, Syk, and PLCγ2, as well as the phosphorylation of PI3K, AKT, and mitogen-activated protein kinases (MAPKs). The inhibitory effect of <italic>C. fragile</italic> resulted from an inhibition of platelet αIIbβ3 integrin outside-in signal transduction during cell activation. Oral administration of <italic>C. fragile</italic> efficiently blocked FeCl<sub>3</sub>-induced arterial thrombus formation <italic>in vivo</italic> without prolonging bleeding time. GC-MS analysis revealed that phytol was the main constituent and the total content of isomers was 160.8 mg/kg. Our results demonstrated that <italic>C. fragile</italic> suppresses not only the inside-out signaling of αIIbβ3 integrin but also outside-in signal transmission. Therefore, <italic>C. fragile</italic> could be an effective antiplatelet therapeutic candidate.</p>