Ginkgolide C inhibits platelet aggregation in cAMP- and cGMP-dependent manner by activating MMP-9.
In this report, we investigated the effect of ginkgolide C (GC) from Ginkgo biloba leaves in collagen (10 mug/ml)-stimulated platelet aggregation. It has been known that matrix metalloproteinase-9 (MMP-9) is released from human platelets, and that it significantly inhibited platelet aggregation stimulated by collagen. Zymographic analysis confirmed that pro-MMP-9 (92-kDa) was activated by GC to form an activated MMP-9 (86-kDa) on gelatinolytic activities. And then, GC dose-dependently inhibited platelet aggregation, intracellular Ca(2+) mobilization, and thromboxane A(2) (TXA(2)) formation in collagen-stimulated platelets. In addition, GC significantly increased the formation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which have an anti-platelet function in both resting and collagen-stimulated platelets. Therefore, we demonstrate that the inhibitory effect of GC on platelet aggregation might be involved into the following pathways. GC may increase intracellular cAMP and cGMP production and MMP-9 activity, inhibit intracellular Ca(2+) mobilization and TXA(2) production, thereby leading to inhibition of platelet aggregation. These results strongly indicate that GC is a potent inhibitor of collagen-stimulated platelet aggregation. It may be a suitable tool for a negative regulator during platelet activation.
Cho
Hyun-Jeong
HJ
Department of Herbal Pharmacology, College of Oriental Medicine and Cardiovascular Medical Research Center, Dongguk University, Sukjang-Dong 707, Gyeongju 780-714, Korea.
Shon
Yun-Hee
YH
Nam
Kyung-Soo
KS
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology*; D046934:Ginkgolides / Q000494:pharmacology*; D066298:In Vitro Techniques; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013928:Thromboxane A2 / Q000096:biosynthesis
D046934:Ginkgolides; D007783:Lactones; D010936:Plant Extracts; C058295:ginkgolide C; D013928:Thromboxane A2; D003094:Collagen; D000242:Cyclic AMP; D020780:Matrix Metalloproteinase 9; D006152:Cyclic GMP; D002118:Calcium