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Telomerase Reverse Transcriptase Deficiency Prevents Neointima Formation Through Chromatin Silencing of E2F1 Target Genes.
Endorf, Elizabeth B; Qing, Hua; Aono, Jun; Terami, Naoto; Doyon, Geneviève; Hyzny, Eric; Jones, Karrie L; Findeisen, Hannes M; Bruemmer, Dennis.
Afiliación
  • Endorf EB; From the Saha Cardiovascular Research Center, and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington (E.B.E., H.Q., J.A., K.L.J., H.M.F.); and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, UPMC and University
  • Qing H; From the Saha Cardiovascular Research Center, and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington (E.B.E., H.Q., J.A., K.L.J., H.M.F.); and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, UPMC and University
  • Aono J; From the Saha Cardiovascular Research Center, and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington (E.B.E., H.Q., J.A., K.L.J., H.M.F.); and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, UPMC and University
  • Terami N; From the Saha Cardiovascular Research Center, and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington (E.B.E., H.Q., J.A., K.L.J., H.M.F.); and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, UPMC and University
  • Doyon G; From the Saha Cardiovascular Research Center, and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington (E.B.E., H.Q., J.A., K.L.J., H.M.F.); and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, UPMC and University
  • Hyzny E; From the Saha Cardiovascular Research Center, and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington (E.B.E., H.Q., J.A., K.L.J., H.M.F.); and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, UPMC and University
  • Jones KL; From the Saha Cardiovascular Research Center, and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington (E.B.E., H.Q., J.A., K.L.J., H.M.F.); and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, UPMC and University
  • Findeisen HM; From the Saha Cardiovascular Research Center, and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington (E.B.E., H.Q., J.A., K.L.J., H.M.F.); and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, UPMC and University
  • Bruemmer D; From the Saha Cardiovascular Research Center, and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington (E.B.E., H.Q., J.A., K.L.J., H.M.F.); and Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, UPMC and University
Arterioscler Thromb Vasc Biol ; 37(2): 301-311, 2017 Feb.
Article en En | MEDLINE | ID: mdl-27932351
OBJECTIVE: Aberrant proliferation of smooth muscle cells (SMC) in response to injury induces pathological vascular remodeling during atherosclerosis and neointima formation. Telomerase is rate limiting for tissue renewal and cell replication; however, the physiological role of telomerase in vascular diseases remains to be determined. The goal of the present study was to determine whether telomerase reverse transcriptase (TERT) affects proliferative vascular remodeling and to define the molecular mechanism by which TERT supports SMC proliferation. APPROACH AND RESULTS: We first demonstrate high levels of TERT expression in replicating SMC of atherosclerotic and neointimal lesions. Using a model of guidewire-induced arterial injury, we demonstrate decreased neointima formation in TERT-deficient mice. Studies in SMC isolated from TERT-deficient and TERT overexpressing mice with normal telomere length established that TERT is necessary and sufficient for cell proliferation. TERT deficiency did not induce a senescent phenotype but resulted in G1 arrest albeit hyperphosphorylation of the retinoblastoma protein. This proliferative arrest was associated with stable silencing of the E2F1-dependent S-phase gene expression program and not reversed by ectopic overexpression of E2F1. Finally, chromatin immunoprecipitation and accessibility assays revealed that TERT is recruited to E2F1 target sites and promotes chromatin accessibility for E2F1 by facilitating the acquisition of permissive histone modifications. CONCLUSIONS: These data indicate a previously unrecognized role for TERT in neointima formation through epigenetic regulation of proliferative gene expression in SMC.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Telomerasa / Silenciador del Gen / Ensamble y Desensamble de Cromatina / Aterosclerosis / Factor de Transcripción E2F1 / Lesiones del Sistema Vascular / Neointima / Músculo Liso Vascular Tipo de estudio: Prognostic_studies Idioma: En Revista: Arterioscler Thromb Vasc Biol Asunto de la revista: ANGIOLOGIA Año: 2017 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Telomerasa / Silenciador del Gen / Ensamble y Desensamble de Cromatina / Aterosclerosis / Factor de Transcripción E2F1 / Lesiones del Sistema Vascular / Neointima / Músculo Liso Vascular Tipo de estudio: Prognostic_studies Idioma: En Revista: Arterioscler Thromb Vasc Biol Asunto de la revista: ANGIOLOGIA Año: 2017 Tipo del documento: Article