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目的观察西洛他唑对糖尿病大鼠主动脉血管细胞粘附分子-1(VCAM-1)、核因子(NF)-κB及过氧化物酶增殖体激活受体(PPAR s)的影响,探讨西洛他唑影响VCAM-1表达的上游信号通路。方法腹腔注射链脲佐菌素(65 mg.kg-1)制备糖尿病模型,正常对照组大鼠腹腔注射柠檬酸钠缓冲液(NC,n=8)。随机将成模的32只糖尿病大鼠分为糖尿病模型组(DM,n=12)、高剂量西洛他唑组(GX,27mg.kg-1.d-1,n=10)与低剂量西洛他唑组(DX,9 mg.kg-1.d-1,n=10)。治疗8 wk,采用免疫组织化学法检测各组主动脉组织VCAM-1表达及P65亚基核转位情况;原位杂交和凝胶电泳迁移率改变分析法(EMSA)检测主动脉VCAM-1 mRNA表达及NF-κB-DNA结合活性;RT-PCR或Real-Time PCR检测PPARα、PPARγmRNA表达。结果①与正常组相比,糖尿病大鼠主动脉内皮VCAM-1及其基因表达升高(P<0.01),NF-κB P65核转位及活化增强(P<0.01),PPARγmRNA表达为正常大鼠的1.7倍,而PPARαmRNA表达下降(P<0.01)。②与糖尿病组相比,高剂量西洛他唑治疗组主动脉内皮VCAM-1及其基因表达降低(P<0.01),NF-κB P65核转位及活化被抑制(P<0.01),PPARγmRNA表达比糖尿病大鼠下降73%,而PPARαmRNA则上升(P<0.05)。结论高剂量西洛他唑抑制糖尿病大鼠主动脉内皮表达VCAM-1,这可能与其对PPARs表达、NF-κB核转位及其DNA结合活性的影响有关。
Objective To investigate the effect of cilostazol on the expression of vascular cell adhesion molecule-1 (VCAM-1), nuclear factor (NF) -κB and peroxisome proliferator activated receptor (PPARs) in diabetic rats Cilostazol Affects the Upstream Signaling Pathway of VCAM-1 Expression. Methods Diabetic model was induced by intraperitoneal injection of streptozotocin (65 mg.kg-1). The normal control rats were injected intraperitoneally with sodium citrate buffer (NC, n = 8). Thirty-two diabetic rats randomly divided into diabetic model group (DM, n = 12), high dose cilostazol group (GX, 27mg.kg-1.d-1, n = 10) and low dose The losartazole group (DX, 9 mg.kg-1.d-1, n = 10). The expression of VCAM-1 and the subunit nuclear translocation of P65 in each group were detected by immunohistochemistry. The expression of VCAM-1 mRNA in aorta was detected by in situ hybridization and electrophoretic mobility shift assay (EMSA) Expression and NF-κB-DNA binding activity; PPARα, PPARγ mRNA expression was detected by RT-PCR or Real-Time PCR. Results ① Compared with the normal group, the expression of VCAM-1 and its gene in the aorta of diabetic rats increased (P <0.01), the nuclear translocation and activation of NF-κB P65 increased (P <0.01), and the expression of PPARγmRNA was normal 1.7-fold, while PPARαmRNA expression decreased (P <0.01). ②Compared with diabetic group, the expression of VCAM-1 and its gene in the aorta of high-dose cilostazol group decreased (P <0.01), nuclear translocation and activation of NF-κB P65 was inhibited (P <0.01), and PPARγmRNA Compared with diabetic rats, the expression level of PPARαmRNA increased by 73% (P <0.05). Conclusion High dose cilostazol can inhibit the expression of VCAM-1 in the aortic endothelium of diabetic rats, which may be related to its effect on PPARs expression, nuclear translocation of NF-κB and DNA binding activity.