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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 observe the effects of cariporide, a selective inhibitor of Na + / H + exchange 1 (NHE1), on neointima formation after carotid artery balloon injury in advanced glycation end products (AGEs) The injured part of the common carotid artery was injured by balloon, the specimens were stained with HE for morphological observation and the intima / media area and intima / media area ratio were calculated.In order to explore the related mechanism, primary cultured rat The proliferation of VSMCs was detected by using vascular smooth muscle cells (VSMC) and [3H] thymidine. The expressions of MMP-2, MMP-9 and MMP- -9, MMP-9 and COX-2 mRNA were detected by Western blot. The expression of nuclear factor kappa B (NF-κB) and the degradation of IκBα were detected by Western blot. Cariporide (0.1, 10 mg / kg) significantly inhibited neointima hyperplasia induced by AGEs after balloon injury in rat carotenoids (P <0.01). The results of cell experiments showed that cariporide could inhibit AGEs-induced COX -2, MMP-2 and MMP-9 mRNA expression, significantly inhibited the degradation of I-κBα and NF- B expression.The results showed that cariporide could significantly inhibit the formation of neointima induced by AGEs after vascular injury and its mechanism was related to the inhibition of NHE1 activity and the inhibition of NF-κB activation and down-regulation of MMP-2, MMP-9 and COX-2 mRNA. It is suggested that NHE1 may be an important part of AGEs induced vascular injury signaling pathway.