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Telomerase deficiency in bone marrow-derived cells attenuates angiotensin II-induced abdominal aortic aneurysm formation.

Authors :
Findeisen HM
Gizard F
Zhao Y
Cohn D
Heywood EB
Jones KL
Lovett DH
Howatt DA
Daugherty A
Bruemmer D
Source :
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2011 Feb; Vol. 31 (2), pp. 253-60. Date of Electronic Publication: 2010 Nov 18.
Publication Year :
2011

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.<br />Methods and 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.<br />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.

Details

Language :
English
ISSN :
1524-4636
Volume :
31
Issue :
2
Database :
MEDLINE
Journal :
Arteriosclerosis, thrombosis, and vascular biology
Publication Type :
Academic Journal
Accession number :
21088250
Full Text :
https://doi.org/10.1161/ATVBAHA.110.218545