Influence of 3-Hydroxy-3-Methylglutaryl-CoA Reductase Inhibitors on ICAM-1 Gene Induction and the Formation of Oxidants in Endothelial Cells

• Main Authors: Sheng-Ping Chang, 張聖平
• Other Authors: Being-Sun Wung
• Format: Others
• Language: zh-TW
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/11544777211102514671

碩士 === 國立嘉義大學 === 生物科技研究所 === 92 === ABSTRACT Statins, HMG-CoA reductase inhibitors, in addition to cholesterol-lowering effects, have inhibitory effect in isoprenoid synthesis, which is required for the modification of Rho and increase NO production. However, under some conditions the statins-increased NO production may react with superoxide to promote peroxynitrite formation, increasing the possibility of tissue injury. In this study, we examine the high dose treatment of statins on ICAM-1 gene induction in endothelial cells (ECs). Statins treated ECs increase intercellular ROS levels. ECs pretreated with lovastatin or mevastatin partially inhibit TNF-induced ICAM-1 gene expression, but they also promote the basal level of ICAM-1 gene expression. Pretreatment with antioxidant, NAC on cell, the lovastatin-induced ICAM-1 gene expression is reduced. Using mutation analysis of ICAM-1 promoter, we find lovastatin- increased ICAM-1 promoter activity is mediated through NF-kB activation. The induction of ICAM-1 promoter activity is reversed by the addition of mevalonate, GGPP or NO synthase inhibitor, L-NAME implicating that statins influence ICAM-1 gene expression via isoprenylation and NO production. These findings suggest that the statins may induce ICAM-1 gene expression via the increased NO production resulting of increase of intracellular ROS level.