title: Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective.
abstract: Although somatic cell activation of the embryonic stem cell (ESC) pluripotency factor OCT4 has been reported, this previous work has been controversial and has not demonstrated a functional role for OCT4 in somatic cells. Here we demonstrate that smooth muscle cell (SMC)-specific conditional knockout of Oct4 in Apoe(-/-) mice resulted in increased lesion size and changes in lesion composition that are consistent with decreased plaque stability, including a thinner fibrous cap, increased necrotic core area, and increased intraplaque hemorrhage. Results of SMC-lineage-tracing studies showed that these effects were probably the result of marked reductions in SMC numbers within lesions and SMC investment within the fibrous cap, which may result from impaired SMC migration. The reactivation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was hypoxia inducible factor-1α (HIF-1α, encoded by HIF1A) and Krüppel-like factor-4 (KLF4)-dependent. These results provide the first direct evidence that OCT4 has a functional role in somatic cells, and they highlight the potential role of OCT4 in normal and diseased somatic cells.
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Cherepanova
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.|Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Delphine
authors.initials: D
authors.lastname: Gomez
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.|Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Shankman
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.|Intercollegiate Faculty of Biotechnology, University of Gdansk, Gdansk, Poland.
authors.forename: Pamela
authors.initials: P
authors.lastname: Swiatlowska
authors.affiliation: The Center for Cardiovascular Biology and Atherosclerosis Research, University of Texas Houston Medical School, Houston, Texas, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Williams
authors.affiliation: Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Olga F
authors.initials: OF
authors.lastname: Sarmento
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.|Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Gabriel F
authors.initials: GF
authors.lastname: Alencar
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.|Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hess
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Bevard
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Greene
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.|Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Meera
authors.initials: M
authors.lastname: Murgai
authors.affiliation: Bioinformatics Core, School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Turner
authors.affiliation: The Center for Cardiovascular Biology and Atherosclerosis Research, University of Texas Houston Medical School, Houston, Texas, USA.
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Geng
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bekiranov
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.|Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Connelly
authors.affiliation: Institute of Cytology, Russian Academy of Science, Saint Petersburg, Russia.
authors.forename: Alexey
authors.initials: A
authors.lastname: Tomilin
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.|Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Owens
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics*; D015153:Blotting, Western; D019070:Cell Lineage; D002465:Cell Movement / Q000235:genetics*; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D003324:Coronary Artery Disease / Q000378:metabolism; D066273:Diet, Western; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics* / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001057:Apolipoproteins E; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C494174:Pou5f1 protein, mouse