Wang Shuang Xi, Sun Xue Ying, Zhang Xiao Hong, Chen Shuang Xiu, Liu Yu Hui, Liu Li Ying
Department of Pharmacology, Pharmaceutical College, Central South University, Changsha, HN 410078, China.
Life Sci. 2006 Aug 29;79(14):1399-404. doi: 10.1016/j.lfs.2006.04.008. Epub 2006 Apr 25.
The aim of this study was to examine whether cariporide, a new inhibitor of Na(+)/H(+) exchanger 1 (NHE-1), may inhibit high glucose-induced monocyte-endothelial cell adhesion and the expression of intercellular adhesion molecule-1 (ICAM-1). Cultured endothelial cells were incubated with normal glucose control (5.5 mM), cariporide control (5.5 mM glucose plus 10 microM cariporide), hyperosmolarity (5.5 mM glucose plus 16.5 mM mannitol), high glucose (HG, 22 mM), low-concentration cariporide (22 mM glucose plus 0.1 microM cariporide), medium-concentration cariporide (22 mM glucose plus 1 muM cariporide), and high-concentration cariporide (22 mM glucose plus 10 microM cariporide) for 24 h. Monocytes were isolated from peripheral human blood. Adhered monocytes were quantified by measuring their protein content. ICAM-1 expression and NHE-1 activity was determined with enzyme-linked immunosorbent assay (ELISA) and pH-sensitive fluorescent spectrophotometry. Exposure of endothelial cells to HG for 24 h caused an increase of adhesion of monocytes to endothelial cells and an increased expression of ICAM-1. However, these effects were reversed by treatment with cariporide (0.1, 1, 10 microM) in a concentration-dependent manner. Furthermore, cariporide (1 microM) was able to inhibit the activation of NHE-1 induced by HG in endothelial cells. These findings suggest that cariporide might inhibit HG-mediated monocyte-endothelial cell adhesion and expression of ICAM-1 by inhibiting the activation of NHE-1.
本研究的目的是检测新型钠氢交换体1（NHE-1）抑制剂卡里波罗是否能抑制高糖诱导的单核细胞与内皮细胞的黏附以及细胞间黏附分子1（ICAM-1）的表达。将培养的内皮细胞分别与正常葡萄糖对照（5.5 mM）、卡里波罗对照（5.5 mM葡萄糖加10 μM卡里波罗）、高渗溶液（5.5 mM葡萄糖加16.5 mM甘露醇）、高糖（HG，22 mM）、低浓度卡里波罗（22 mM葡萄糖加0.1 μM卡里波罗）、中浓度卡里波罗（22 mM葡萄糖加1 μM卡里波罗）和高浓度卡里波罗（22 mM葡萄糖加10 μM卡里波罗）孵育24小时。从人外周血中分离单核细胞。通过测量其蛋白质含量对黏附的单核细胞进行定量。采用酶联免疫吸附测定（ELISA）和pH敏感荧光分光光度法测定ICAM-1的表达和NHE-1的活性。内皮细胞暴露于高糖24小时会导致单核细胞与内皮细胞黏附增加以及ICAM-1表达增加。然而，用卡里波罗（0.1、1、10 μM）处理可呈浓度依赖性逆转这些效应。此外，卡里波罗（1 μM）能够抑制高糖诱导的内皮细胞中NHE-1的激活。这些发现表明，卡里波罗可能通过抑制NHE-1的激活来抑制高糖介导的单核细胞与内皮细胞的黏附以及ICAM-1的表达。
