Department of Pharmacology, College of Pharmacy & Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 305-764, Republic of Korea.
Eur J Pharmacol. 2011 Jan 10;650(1):342-9. doi: 10.1016/j.ejphar.2010.10.046. Epub 2010 Oct 30.
We have previously reported that fenofibrate displayed a potent antithrombotic effect by the inhibition of platelet aggregation. The present study was designed to investigate the effects of fenofibrate on the neointimal hyperplasia and its possible molecular mechanism. Neointimal hyperplasia was measured in balloon-inflated-induced vascular injury model of male Sprague-Dawley rats and cell proliferation was measured in primary cultured rat aortic vascular smooth muscle cells (VSMCs). Fenofibrate-treated group showed a significant reduction in neointimal formation (0.07±0.04mm(2)) from the control (0.13±0.04mm(2)). Fenofibrate significantly inhibited platelet-derived growth factor (PDGF)-BB-induced cell counting and [(3)H]-thymidine incorporation into DNA. Fenofibrate suppressed the PDGF-BB-inducible progression through G(0)/G(1) to S phase of cell cycle. Moreover, fenofibrate inhibited not only phosphorylation of retinoblastoma (Rb) protein and expression of cyclin D/E, CDK 2/4 and proliferating cell nuclear antigen (PCNA) proteins but also mitogen-activated protein kinase (MAPK) signaling pathways such as ERK 1/2, p38 and JNK phosphorylation. In conclusion, the present study demonstrates that fenofibrate significantly inhibits neointimal formation via G(0)/G(1) arrest of PDGF-BB-induced cell proliferation in association with the inhibition of MAPK, which resulted in the downregulation of expressions of cyclin D/E, CDK 2/4 and PCNA proteins, suggesting that fenofibrate may be useful for individuals with a high risk of thrombotic or cardiovascular diseases.
我们之前的研究报道，非诺贝特通过抑制血小板聚集，显示出很强的抗血栓作用。本研究旨在探讨非诺贝特对血管内膜增生的作用及其可能的分子机制。采用雄性 Sprague-Dawley 大鼠球囊损伤血管模型检测血管内膜增生，采用原代培养的大鼠主动脉血管平滑肌细胞（VSMCs）检测细胞增殖。结果显示，非诺贝特治疗组血管内膜增生（0.07±0.04mm2）较对照组（0.13±0.04mm2）明显减少。非诺贝特显著抑制血小板衍生生长因子（PDGF）-BB 诱导的细胞计数和[3H]-胸苷掺入 DNA。非诺贝特抑制 PDGF-BB 诱导的细胞周期从 G0/G1 期到 S 期的进展。此外，非诺贝特不仅抑制视网膜母细胞瘤（Rb）蛋白的磷酸化和细胞周期蛋白 D/E、CDK 2/4 和增殖细胞核抗原（PCNA）蛋白的表达，还抑制丝裂原激活蛋白激酶（MAPK）信号通路如 ERK 1/2、p38 和 JNK 的磷酸化。综上所述，本研究表明，非诺贝特通过抑制 PDGF-BB 诱导的细胞增殖的 G0/G1 期阻滞，显著抑制血管内膜增生，与 MAPK 的抑制有关，导致细胞周期蛋白 D/E、CDK 2/4 和 PCNA 蛋白表达下调，提示非诺贝特可能对血栓或心血管疾病高危人群有用。
