title: Telomerase deficiency in bone marrow-derived cells attenuates angiotensin II-induced abdominal aortic aneurysm formation.
abstract: OBJECTIVE
  Abdominal aortic aneurysms (AAA) are an age-related vascular disease and an important cause of morbidity and mortality. In this study, we sought to determine whether the catalytic component of telomerase, telomerase reverse transcriptase (TERT), modulates angiotensin (Ang) II-induced AAA formation.
  
  
  RESULTS
  Low-density lipoprotein receptor-deficient (LDLr-/-) mice were lethally irradiated and reconstituted with bone marrow-derived cells from TERT-deficient (TERT-/-) mice or littermate wild-type mice. Mice were placed on a diet enriched in cholesterol, and AAA formation was quantified after 4 weeks of Ang II infusion. Repopulation of LDLr-/- mice with TERT-/- bone marrow-derived cells attenuated Ang II-induced AAA formation. TERT-deficient recipient mice revealed modest telomere attrition in circulating leukocytes at the study end point without any overt effect of the donor genotype on white blood cell counts. In mice repopulated with TERT-/- bone marrow, aortic matrix metalloproteinase-2 (MMP-2) activity was reduced, and TERT-/- macrophages exhibited decreased expression and activity of MMP-2 in response to stimulation with Ang II. Finally, we demonstrated in transient transfection studies that TERT overexpression activates the MMP-2 promoter in macrophages.
  
  
  CONCLUSIONS
  TERT deficiency in bone marrow-derived macrophages attenuates Ang II-induced AAA formation in LDLr-/- mice and decreases MMP-2 expression. These results point to a previously unrecognized role of TERT in the pathogenesis of AAA.
authors.affiliation: Saha Cardiovascular Research Center, University of Kentucky, 900 S Limestone St., Lexington, KY 40536-0200, USA.
authors.forename: Hannes M
authors.initials: HM
authors.lastname: Findeisen
authors.forename: Florence
authors.initials: F
authors.lastname: Gizard
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Dianne
authors.initials: D
authors.lastname: Cohn
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Heywood
authors.forename: Karrie L
authors.initials: KL
authors.lastname: Jones
authors.forename: David H
authors.initials: DH
authors.lastname: Lovett
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Howatt
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced* / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D002478:Cells, Cultured; D004549:Elastin / Q000378:metabolism; D005838:Genotype; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000172:deficiency* / Q000235:genetics; D016615:Telomere
chemical_list: D011973:Receptors, LDL; D000804:Angiotensin II; D004549:Elastin; D019098:Telomerase; C509187:Tert protein, mouse; D020778:Matrix Metalloproteinase 2