title: Telomerase Reverse Transcriptase Deficiency Prevents Neointima Formation Through Chromatin Silencing of E2F1 Target Genes.
abstract: 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.
  
  
  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.
authors.affiliation: 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 of Pittsburgh School of Medicine, PA (N.T., G.D., E.H., D.B.).
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Endorf
authors.affiliation: 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 of Pittsburgh School of Medicine, PA (N.T., G.D., E.H., D.B.).
authors.forename: Hua
authors.initials: H
authors.lastname: Qing
authors.affiliation: 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 of Pittsburgh School of Medicine, PA (N.T., G.D., E.H., D.B.).
authors.forename: Jun
authors.initials: J
authors.lastname: Aono
authors.affiliation: 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 of Pittsburgh School of Medicine, PA (N.T., G.D., E.H., D.B.).
authors.forename: Naoto
authors.initials: N
authors.lastname: Terami
authors.affiliation: 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 of Pittsburgh School of Medicine, PA (N.T., G.D., E.H., D.B.).
authors.forename: Geneviève
authors.initials: G
authors.lastname: Doyon
authors.affiliation: 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 of Pittsburgh School of Medicine, PA (N.T., G.D., E.H., D.B.).
authors.forename: Eric
authors.initials: E
authors.lastname: Hyzny
authors.affiliation: 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 of Pittsburgh School of Medicine, PA (N.T., G.D., E.H., D.B.).
authors.forename: Karrie L
authors.initials: KL
authors.lastname: Jones
authors.affiliation: 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 of Pittsburgh School of Medicine, PA (N.T., G.D., E.H., D.B.).
authors.forename: Hannes M
authors.initials: HM
authors.lastname: Findeisen
authors.affiliation: 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 of Pittsburgh School of Medicine, PA (N.T., G.D., E.H., D.B.). bruemmerd@upmc.edu.
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
mesh_terms: D000107:Acetylation; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001665:Binding Sites; D049109:Cell Proliferation; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005263:Femoral Artery / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D059585:G1 Phase Cell Cycle Checkpoints; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D019098:Telomerase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D066253:Vascular Remodeling; D057772:Vascular System Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D006657:Histones; D016160:Retinoblastoma Protein; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse
keywords: cell proliferation; epigenesist; myocytes; neointima; smooth muscle; telomerase; vascular remodeling