Role for Telomerase in Pulmonary Hypertension
Background—Cells exhibiting dysregulated growth may express telomerase reverse transcriptase (TERT), whose dual function consists in 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 and/or activity were 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 upon 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 (G2) and TERT-/- mice at G2, G3, and G4 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 two 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.
- Received September 14, 2014.
- Revision received December 1, 2014.
- Accepted December 19, 2014.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License (http://creative commons.org/licenses/by-nc/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.