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ȣ - 500343 118 |
| JS6784, a Biphenolic Component of Natural Leaves, Inhibits Rat Aortic Vascular Smooth Muscle Cell Growth by Induction of p21WAF1/CIP1 and Neointimal Hyperplasia in a Rat Carotid Artery Injury Model |
| 충북대학교병원 순환기내과¹ 충북대학교 약학대학² |
| 권진숙¹, 임용², 박노관¹, 김유경¹, 정일하¹, 윤여표², 배장환¹, 황경국¹, 김동운¹, 조명찬¹ |
Background and Objectives: JS6784, a biphenolic component from natural leaves, displays anti-platelet, anti-fungal, anti-bacterial, anti-inflammatory and Acyl-CoA : Cholesterol Acyltransferase inhibitory effects. In this study, we focused on the antiproliferative action of JS6784. In vitro, we investigated its effects on rat aortic vascular smooth muscle cells (VSMCs) stimulated by the platelet-derived growth factor (PDGF)-BB. In vivo, we tested whether perivascular delivery of JS6784 can prevent neointimal formation via histologic and angiographic assessment in a rat carotid artery injury model. Methods and Results: JS6784 potently inhibited the growth of rat aortic VSMCs induced by PDGF-BB in a dose-dependent manner. JS6784 also strongly inhibited the DNA synthesis induced by PDGF-BB in a dose-dependent manner. In order to elucidate the inhibitory mechanism of VSMCs growth, cell cycle progression, apoptosis and signaling pathway were also investigated. JS6784 had no effects on PDGF-BB-induced intracellular early signal transductions such as extracellular response kinases 1 and 2 (ERK1/2), phosphatidylinositol 3'-kinase (PI3'-K)/Akt and phospholipase C-γ1 (PCL-γ1). JS6784 blocked the PDGF-BB-induced progression through G0/G1 to S phase of the cell cycle in synchronized cells without apoptosis. JS6784 significantly increased intracellular p21WAF1/CIP1 levels in a dose-dependent manner. Fifteeen days after injury, the angiographic mean luminal diameter of the JS6784-treated group (n=7, 0.78 ± 0.11 arbitrary unit) was significantly larger than that of the control (n=12, 0.63 ± 0.12 AU). JS6784-treated group showed a significant neointimal formation reduction versus the control group (0.13 ± 0.04 mm2 versus 0.17 ± 0.09 mm2, p<0.05). Conclusion: This study suggests that JS6784 may inhibit the proliferation of rat aortic VSMCs proliferation by perturbing cell cycle progression, which may be due to the activation of p21WAF1/CIP1 pathway. We also have demonstrated that perivascular application of JS6784 provides an effective means of inhibiting proliferative response to vascular injury in the rat.
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