title: Telmisartan exerts pleiotropic effects in endothelial cells and promotes endothelial cell quiescence and survival.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Telmisartan exerts antiproliferative and antiapoptotic effects in ECs. This may account for the improved endothelial dysfunction observed in the clinical setting.
authors.affiliation: Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Mauro
authors.initials: M
authors.lastname: Siragusa
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001798:Blood Proteins / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D007653:Ketocholesterols / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D001798:Blood Proteins; D018797:Cell Cycle Proteins; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007653:Ketocholesterols; C548840:telmisartan amlodipine combination; D017311:Amlodipine; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C003001:7-ketocholesterol; D000077333:Telmisartan
keywords: Akt protein, human; apoptosis; endothelial cells; growth; telmisartan