PI3K, Akt, p38을 포함한 인산화단백질에 대한 Cordycepin의 억제효과
The Inhibitory Effects of Cordycepin on Phosphoproteins including PI3K, Akt, and p38
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진균 속에 속하는 종인 Cordyceps 는 중국의 전통약제로서, 그 유효성분인 cordycepin이 혈소판 응집에 관여한다는 보고가 있지만 phosphoprotein 조절에 관련된 연구는 미흡하다. 본 연구에서는, cordycepin이 fibrinogen binding에 관여한다고 알려진 PI3k/Akt와 TXA2 분비 및 과립방출에 관여한다고 알려진 p38와 같은 phosphoprotein의 인산화를 어떻게 조절하며 혈소판응집을 억제시키는지 규명하고자 하였다. 그 결과, cordycepin가 261.1 μM 의 IC50으로 collagen이 유도한 혈소판 응집을 강력하게 억제하였고, PI3K와 Akt의 인산화를 감소시키며 αIIb/β3에 대한 fibrinogen 결합을 농도의존적으로 억제하였다. 또한, cordycepin은 collagen이 촉진시킨 p38의 인산화를 억제함으로써, 과립방출의 지표인 ATP 과 serotonin의방출을 억제하였고 COX-1과 TXAS의 활성 및 PLC-γ2 인산화에 대한 영향없이 TXA2 생성량을 감소시켰다. 따라서, cordycepin은 PI3K/Akt, p38와 같은 phosphoprotein의 인산화를 억제함으로써 혈소판 응집억제를 나타내는 항혈전 치료및 예방약물로서 유용한 가치가 있다고 여겨진다.
Abstract
A species of Cordyceps, an ingredient in Chinese traditional medicine well-known for its major component, cordycepin (3'-deoxyadenosine), has been known to have antiplatelet effects; however, its effects on regulation of phosphoprotein have not been fully elucidated. In this study, we investigated how cordycepin regulates the phosphoprotein, including phosphatidylinositol 3-kinase (PI3K)/Akt and p38, to inhibit platelet aggregation, which are concerned with fibrinogen binding to glycoprotein IIb/IIIa (αIIb/β3) and granule secretion in platelets. Our finding suggests that cordycepin inhibits collagen-induced platelet aggregation with 261.1 μM of IC50 and also inhibits fibrinogen binding to αIIb/β3 by a suppression of PI3K/Akt phosphorylation in a dose dependent manner. In addition, cordycepin further showed to inhibit collagen-induced p38 phosphorylation, reducing granule secretion (i.e. ATP- and serotonin-release) and thromboxane A2 (TXA2) production without regulating cyclooxygenase-1 (COX-1) and thromboxane A synthase (TXAS) activities, as well as phospholipase C-γ2 (PLC-γ2) phosphorylation. In conclusion, these results demonstrate that cordycepin-mediated antiplatelet effects were due to the inhibition of fibrinogen binding to αIIb/β3 via the suppression of PI3K/Akt phosphorylation and inhibition of granule secretion & TXA2 production by suppressing p38 phosphorylation. These results strongly indicate that cordycepin might have therapeutic or preventive potential for platelet aggregation- mediated disorders, regulating the phosphoprotein, including PI3K/Akt and p38.
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