title: Atorvastatin induces T cell proliferation by a telomerase reverse transcriptase (TERT) mediated mechanism.
abstract: Statins are one of the most potent drugs in delaying age-related inflammatory changes in the arterial vessel wall, slowing down the progression of atherosclerosis. Statins have also been shown to abrogate telomere-attributed cardiovascular risk. The goal of our study was to explore a potential effect of atorvastatin on telomerase activity in peripheral blood mononuclear cells (PBMCs) and T-lymphocytes (T cells).
  
  
  RESULTS
  Treatment with pharmacologically relevant concentrations (0.1-0.3 μM) of atorvastatin resulted in a 6-fold increase of telomerase activity (TA) (p < 0.0001) in human and mouse PBMCs and CD4 T cells, translating into moderate proliferation of T lymphocytes. In contrast, high doses of atorvastatin (2-5 μM) or the addition of LDL cholesterol completely inhibited proliferation, thereby abrogating telomerase activity. The proliferative effect of atorvastatin was ablated by the absense of the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT). Using transgenic GFP-mTert reporter mice, we observed a decrease in telomerase-positive lymphocytes from 30% to 15% during the first 5 months of age (p < 0.01). This suggests that the decrease in immune cell turnover during normal development and maturation is mirrored by a reduction in telomerase activity in lymphocytes in-vivo.
  
  
  CONCLUSIONS
  Atorvastatin and cholesterol have opposing effects on telomerase in mononuclear cells and T-lymphocytes. Our study suggests a link between cholesterol metabolism and telomere-related cardiovascular risk.
authors.affiliation: Institute of Genetic Medicine at Newcastle University, UK.
authors.forename: Karim
authors.initials: K
authors.lastname: Bennaceur
authors.affiliation: Institute of Genetic Medicine at Newcastle University, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Atwill
authors.affiliation: Institute of Genetic Medicine at Newcastle University, UK.
authors.forename: Nayef
authors.initials: N
authors.lastname: Al Zhrany
authors.affiliation: Institute of Genetic Medicine at Newcastle University, UK.
authors.forename: Jedrzej
authors.initials: J
authors.lastname: Hoffmann
authors.affiliation: Institute of Genetic Medicine at Newcastle University, UK.
authors.forename: Bernard
authors.initials: B
authors.lastname: Keavney
authors.affiliation: Department of Pediatrics, Childrens Hospital and Harvard Stem Cell Institute, Cambridge, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Breault
authors.affiliation: Institute of Genetic Medicine at Newcastle University, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Richardson
authors.affiliation: Institute of Ageing and Health at Newcastle University, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: von Zglinicki
authors.affiliation: Institute of Ageing and Health at Newcastle University, UK.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Saretzki
authors.affiliation: Institute of Genetic Medicine at Newcastle University, UK. Electronic address: ioakim.spyridopoulos@ncl.ac.uk.
authors.forename: Ioakim
authors.initials: I
authors.lastname: Spyridopoulos
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D002318:Cardiovascular Diseases / Q000453:epidemiology; D020134:Catalytic Domain; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D017930:Genes, Reporter; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D012306:Risk; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016615:Telomere / Q000648:ultrastructure; D059505:Telomere Homeostasis / Q000187:drug effects
chemical_list: D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse
keywords: Atorvastatin; Human; Mouse; T-lymphocytes; TERT; Telomerase