Telmisartan Exerts Pleiotropic Effects in Endothelial Cells and Promotes Endothelial Cell Quiescence and Survival

Abstract

Telmisartan, an angiotensin II type 1 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 (ECs), using an unbiased genomic approach. In human umbilical vein ECs, microarray analysis of gene expression followed by pathway enrichment analysis and quantitative polymerase chain reaction validation revealed that telmisartan modulates the expression of key genes responsible for cell cycle progression and apoptosis. Amlodipine's effect was similar to control. ECs 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 angiotensin II type 1 receptor. In telmisartan-treated ECs, phosphorylation and activation of Akt, as well as MDM2, were reduced, leading to accumulation of p53 in the nucleus, where it represses the transcription of cell cycle-promoting genes. Phosphorylation of glycogen synthase kinase-3β was also reduced, resulting in rapid proteolytic turnover of CyclinD1. Telmisartan induced downregulation of proapoptotic genes and protected ECs from serum starvation-induced and 7-ketocholesterol-induced apoptosis. Telmisartan exerts antiproliferative and antiapoptotic effects in ECs. This may account for the improved endothelial dysfunction observed in the clinical setting.