Mouraret Nathalie, Houssaïni Amal, Abid Shariq, Quarck Rozenn, Marcos Elisabeth, Parpaleix Aurelien, Gary-Bobo Guillaume, Dubois-Randé Jean-Luc, Derumeaux Geneviève, Boczkowski Jorge, Delcroix Marion, Blasco Maria A, Lipskaia Larissa, Amsellem Valérie, Adnot Serge
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.).
Circulation. 2015 Feb 24;131(8):742-755. doi: 10.1161/CIRCULATIONAHA.114.013258. Epub 2014 Dec 30.
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.
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.
Telomerase exerts telomere-independent effects on PA-SMC growth in PH and may constitute a treatment target for PH.
生长失调的细胞可能表达端粒酶逆转录酶（TERT），其双重功能包括与RNA模板分子TERC一起维持端粒长度以及控制细胞生长。在此，我们研究了人类和实验性肺动脉高压（PH）中的肺TERT及其在控制肺动脉平滑肌细胞（PA-SMC）增殖中的作用。
在特发性PH患者以及由缺氧或血清素转运体过表达诱导的PH小鼠（SM22-5HTT(+)小鼠）的肺中发现明显的TERT表达或活性，主要在PA-SMC内。在培养的小鼠PA-SMC中，血清刺激生长时TERT表达。TERT抑制剂艾美拉唑和TERT激活剂TA65分别消除和刺激了PA-SMC生长。来自PH小鼠的PA-SMC表现出与TERT表达增加相关的增殖表型增强，艾美拉唑治疗可抑制该表型。第2代TERC(-/-)小鼠以及第2、3和4代TERT(-/-)小鼠发生的PH比暴露于慢性缺氧的野生型小鼠轻，远端肺动脉肌化程度较低，Ki67染色的增殖PA-SMC较少。TERC(-/-)和TERT(-/-)小鼠的端粒长度不同，而这两个品系以及各代的PH严重程度相似。慢性艾美拉唑治疗可减轻野生型小鼠的缺氧诱导的PH，或部分逆转SM22-5HTT(+)小鼠已建立的PH，同时降低TERT表达。用TA65治疗的小鼠则出现相反的效果。
端粒酶对PH中PA-SMC的生长发挥不依赖端粒的作用，可能构成PH的治疗靶点。
