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Circulation. 2015 Feb 24;131(8):742-755. doi: 10.1161/CIRCULATIONAHA.114.013258. Epub 2014 Dec 30.

Role for telomerase in pulmonary hypertension.

Author information

1
INSERM U955, DHU A-TVB and Département de Physiologie, Hôpital Henri Mondor, Créteil, France and Université Paris-Est Créteil, France (N.M., A.H., S.A., E.M., A.P., G.G.-B., G.D., J.B., L.L., V.A., S.A.); Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium (R.Q., M.D.); Service de Cardiologie, Hôpital Henri Mondor and Université Paris-Est Créteil, Créteil, France (J.-L.D.-R.); and Spanish National Cancer Research Centre (CNIO), Telomeres and Telomerase Group, Madrid, Spain (M.A.B.).
#
Contributed equally

Abstract

BACKGROUND:

Cells exhibiting dysregulated growth may express telomerase reverse transcriptase (TERT), the dual function of which consists of maintaining telomere length, in association with the RNA template molecule TERC, and controlling cell growth. Here, we investigated lung TERT in human and experimental pulmonary hypertension (PH) and its role in controlling pulmonary artery smooth muscle cell (PA-SMC) proliferation.

METHODS AND RESULTS:

Marked TERT expression or activity was found in lungs from patients with idiopathic PH and from mice with PH induced by hypoxia or serotonin-transporter overexpression (SM22-5HTT(+) mice), chiefly within PA-SMCs. In cultured mouse PA-SMCs, TERT was expressed on growth stimulation by serum. The TERT inhibitor imetelstat and the TERT activator TA65 abrogated and stimulated PA-SMC growth, respectively. PA-SMCs from PH mice showed a heightened proliferative phenotype associated with increased TERT expression, which was suppressed by imetelstat treatment. TERC(-/-) mice at generation 2 and TERT(-/-) mice at generations 2, 3, and 4 developed less severe PH than did wild-type mice exposed to chronic hypoxia, with less distal pulmonary artery muscularization and fewer Ki67-stained proliferating PA-SMCs. Telomere length differed between TERC(-/-) and TERT(-/-) mice, whereas PH severity was similar in the 2 strains and across generations. Chronic imetelstat treatment reduced hypoxia-induced PH in wild-type mice or partially reversed established PH in SM22-5HTT(+) mice while simultaneously decreasing TERT expression. Opposite effects occurred in mice treated with TA65.

CONCLUSIONS:

Telomerase exerts telomere-independent effects on PA-SMC growth in PH and may constitute a treatment target for PH.

KEYWORDS:

hypertension, pulmonary; muscle; telomerase; vascular remodeling

PMID:
25550449
PMCID:
PMC4824279
DOI:
10.1161/CIRCULATIONAHA.114.013258
[Indexed for MEDLINE]
Free PMC Article

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