Blockade of angiotensin II receptors reduces the expression of receptors for advanced glycation end products in human endothelial cells
Blockade of angiotensin II receptors reduces the expression of receptors for advanced glycation end products in human endothelial cells
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DOI：
10.1161/01.atv.0000239569.99126.37
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发表时间：
2006-10-01
影响因子：
8.7
通讯作者：
Kitakaze, Masafumi
中科院分区：
文献类型：
--
作者：
Fujita, Masashi;Okuda, Hiroko;Kitakaze, Masafumi
目的：晚期糖基化终产物受体（RAGE）在动脉粥样硬化形成中起着关键作用。由于肿瘤坏死因子α（TNF α）在动脉粥样硬化病变中表达并上调TNF α表达，TNF α-TNF α相互作用可能参与动脉粥样硬化形成的炎症过程。另一方面，广泛用作抗高血压药物的血管紧张素II 1型受体阻滞剂（ARB）也被报道具有抗动脉粥样硬化作用。因此，我们研究是否ARB发挥抗动脉粥样硬化作用，通过抑制TNF α-β interaction.Methods和结果-刺激人内皮细胞与坎地沙坦以及奥美沙坦降低TNF α诱导的TNF α的表达在mRNA和蛋白质水平沿着与核因子κ B的活性和炎症介质，如血管细胞粘附分子（VCAM）-1的表达减少。坎地沙坦和奥美沙坦都抑制核因子kappa B与RAGE基因启动子的结合。此外，通过RNA干扰抑制TNF α诱导的VCAM-1在mRNA和蛋白质水平的表达，降低了TNF α诱导的VCAM-1在mRNA和蛋白质水平的基因沉默。阻断血管紧张素II受体可能通过减少TNF α-β相互作用发挥抗动脉粥样硬化作用。
Objectives - Receptors for advanced glycation end products (RAGEs) play crucial roles in atherogenesis. Because tumor necrosis factor alpha (TNF alpha) is expressed and upregulates RAGE expression in atherosclerotic lesions, the TNF alpha-RAGE interaction might be involved in the inflammatory process of atherogenesis. On the other hand, an angiotensin II type-1 receptor blocker (ARB), widely used as an antihypertensive drug, has been reported to have also antiatherosclerotic effects. Thus we investigated whether an ARB exerts antiatherosclerotic effects via inhibiting the TNF alpha-RAGE interaction.Methods and Results - Stimulation of human endothelial cells with candesartan as well as olmesartan decreased TNF alpha-induced RAGE expression in both mRNA and protein levels along with the decrease in the activity of nuclear factor kappa B and the expression of inflammatory mediators such as vascular cell adhesion molecule (VCAM)-1. Both candesartan and olmesartan inhibited the binding of nuclear factor kappa B to the RAGE gene promoter. Furthermore, gene silencing of RAGE by RNA interference decreased the expression of TNF alpha-induced VCAM-1 in both mRNA and protein levels.Conclusions - RAGE contributes at least partially to the TNF alpha-induced VCAM-1 expression in both mRNA and protein levels. Blockade of angiotensin II receptors might exert antiatherosclerotic effects via reducing TNF alpha-RAGE interaction.