卡立泊来德对AGEs所致新内膜形成的抑制作用及相关机制  

Inhibition Effect and Mechanism of Cariporide on Neointimal Proliferation Induced by Advanced Glycation End Products

作　　者：吴树金[1,2] 杨青山[3] 宋涛[2] 周寿红[2] 刘玉辉[2] 刘立英[2] 

机构地区：[1]甘肃省人民医院药剂科,兰州730000 [2]中南大学药学院药理教研室,长沙410078 [3]甘肃省人民医院骨科,兰州730000

出　　处：《生物化学与生物物理进展》2013年第6期531-537,共7页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金资助项目(30600248)~~

摘　　要：为了观察Na+/H+交换蛋白1(NHE1)选择性抑制剂卡立泊来德(cariporide)对糖基化终末产物(advanced glycationend products,AGEs)所致大鼠颈动脉球囊损伤后新内膜形成的作用,以球囊损伤大鼠颈总动脉,取标本HE染色后进行形态学观察并计算内膜、中膜面积及内膜/中膜面积比.为探讨相关机制,原代培养大鼠主动脉平滑肌细胞(vascular smoothmuscle cell,VSMC),[3H]thymidine检测VSMC增殖;RT-PCR及实时RT-PCR检测VSMC基质金属蛋白酶2(matrixmetalloproteinases-2,MMP-2)、基质金属蛋白酶9(matrixmetalloproteinases-9,MMP-9)及环氧酶2(cyclooxygenase-2,COX-2)mRNA水平;Western blot检测核因子κB(NF-κB)的表达及抑制蛋白κBα(I-κBα)的降解.大鼠颈动脉球囊损伤后,cariporide(0.1,10 mg/kg)能显著抑制AGEs所致新内膜增生(P<0.01).细胞实验结果显示,cariporide可以浓度依赖性地抑制AGEs诱导VSMC中COX-2、MMP-2及MMP-9 mRNA表达,同时显著抑制I-κBα降解及NF-κB表达.结果表明,cariporide能显著抑制血管损伤后AGEs所致新内膜的形成,其机制与抑制NHE1活性从而抑制NF-κB活化,下调MMP-2、MMP-9及COX-2 mRNA有关.提示NHE1可能是AGEs致血管损伤信号通路中的重要组成部分.In order to investigate the inhibitory effect of cariporide, a specific Na＋/H＋ exchanger 1 （NHE1） blocker, on neointimal proliferation induced by AGEs in a carotid artery balloon injury model, the rats carotid artery was balloon injured. The exemplars were collected and stained by HE. The morphology changes were observed. The intima area, media area and the ratio of area between intima and media were calculated using image analysis system. In order to explore the precise mechanism, the experiments were done on the isolated rat vascular smooth muscle cells （VSMC）. Cell proliferation was assessed by [3H] thymidine incorporation. RT-PCR and Real-time RT-PCR were used to assay the cyclooxygenase-2 （COX-2） matrix metalloproteinases-2 （MMP-2） and matrix metalloproteinases-9 （MMP-9） expression; Western blot was used to assay NF-κB protein and the degradation of the inhibitor I-κBα. The in vivo results shows that neointima hyperplasia is significantly suppressed treated with cariporide in balloon-injured rats compared with AGEs treatment lonely. The in vitro study shows that cariporide dose-dependently inhibited AGEs-induced upregnlation of COX-2, MMP-2 and MMP-9 expression. We also found that cariporide blocked AGEs-induced activation of nuclear factor-κB （NF-κB）and pointed out that inhibition of NF-κB was achieved by inhibiting the degradation of the inhibitor I-κBα. The results identified that NHE1 inhibitor cariporide inhibited AGEs-induced neointimal hyperplasia in rats balloon-injured model by suppressing the proliferation of VSMC and the upregulation of COX-2, MMP-2 and MMP-9 via inhibiting NF-κB activation in VSMC. These results indicated that NHE1 might be a considerable ingredient of the signal pathway in which AGEs played a key role in the processes of vascular damage.

关 键 词：糖基化终末产物 CARIPORIDE 新内膜形成 NF-ΚB 

分 类 号：R966[医药卫生—药理学]