Telmisartan exerts pleiotropic effects in endothelial cells and promotes endothelial cell quiescence and survival.
Telmisartan exerts pleiotropic effects in endothelial cells and promotes endothelial cell quiescence and survival.
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DOI：
10.1161/atvbaha.112.300985
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发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Sessa WC
中科院分区：
文献类型：
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作者：
Siragusa M;Sessa WC
替米沙坦（一种血管紧张素II 1型（AT 1）受体阻滞剂）和替米沙坦（一种钙通道阻滞剂）是临床上用作单药治疗或联合治疗的抗高血压药物。它们发挥有益的心血管作用，独立于降低血压和经典的作用机制。在这项研究中，我们使用无偏倚的基因组方法研究了替米沙坦和替米沙坦在内皮细胞（EC）中脱靶效应的分子机制。在人脐静脉内皮细胞中，基因表达的微阵列分析以及随后的途径富集分析和定量PCR验证显示，替米沙坦可调节负责细胞周期进展和凋亡的关键基因的表达。Ambassador的效果与对照相似。EC暴露于替米沙坦，而不是ESTA，氯沙坦或缬沙坦，表现出剂量依赖性的细胞生长的损害，并未能进入S期的细胞周期。同样，替米沙坦抑制缺乏AT 1受体的COS-7细胞的增殖。在替米沙坦处理的EC中，Akt和MDM 2的磷酸化和活化减少，导致p53在细胞核中蓄积，在细胞核中抑制细胞周期促进基因的转录。GSK 3 β的磷酸化也减少，导致CyclinD 1的快速蛋白水解周转。替米沙坦诱导促凋亡基因下调，并保护EC免受血清饥饿和7-酮胆固醇诱导的细胞凋亡。替米沙坦在EC中发挥抗增殖和抗凋亡作用。这可以解释在临床环境中观察到的改善的内皮功能障碍。
Telmisartan, an angiotensin II type 1 (AT1) receptor blocker, and amlodipine, a calcium channel blocker, are antihypertensive agents clinically used as monotherapy or in combination. They exert beneficial cardiovascular effects independently of blood pressure lowering and classic mechanisms of action. In this study, we investigate molecular mechanisms responsible for the off-target effects of telmisartan and telmisartan-amlodipine in endothelial cells (EC), using an unbiased genomic approach. In human umbilical vein endothelial cells, microarray analysis of gene expression followed by pathway enrichment analysis and quantitative PCR validation revealed that telmisartan modulates the expression of key genes responsible for cell cycle progression and apoptosis. Amlodipine’s effect was similar to control. EC exposed to telmisartan, but not amlodipine, losartan or valsartan, exhibited a dose-dependent impairment of cell growth and failed to enter the S-phase of the cell cycle. Similarly, telmisartan inhibited proliferation in COS-7 cells lacking the AT1 receptor. In telmisartan-treated EC, phosphorylation and activation of Akt as well as MDM2 was reduced, leading to accumulation of p53 in the nucleus, where it represses the transcription of cell cycle promoting genes. Phosphorylation of GSK3β was also reduced, resulting in rapid proteolytic turnover of CyclinD1. Telmisartan induced downregulation of proapoptotic genes and protected EC from serum starvation- and 7-ketocholesterol-induced apoptosis. Telmisartan exerts antiproliferative and antiapoptotic effects in EC. This may account for the improved endothelial dysfunction observed in the clinical setting.