title: Modulation of cardiac fibrosis by Krüppel-like factor 6 through transcriptional control of thrombospondin 4 in cardiomyocytes.
abstract: OBJECTIVE
  Krüppel-like factors (KLFs) are a family of transcription factors which play important roles in the heart under pathological and developmental conditions. We previously identified and cloned Klf6 whose homozygous mutation in mice results in embryonic lethality suggesting a role in cardiovascular development. Effects of KLF6 on pathological regulation of the heart were investigated in the present study.
  
  
  RESULTS
  Mice heterozygous for Klf6 resulted in significantly diminished levels of cardiac fibrosis in response to angiotensin II infusion. Intriguingly, a similar phenotype was seen in cardiomyocyte-specific Klf6 knockout mice, but not in cardiac fibroblast-specific knockout mice. Microarray analysis revealed increased levels of the extracellular matrix factor, thrombospondin 4 (TSP4), in the Klf6-ablated heart. Mechanistically, KLF6 directly suppressed Tsp4 expression levels, and cardiac TSP4 regulated the activation of cardiac fibroblasts to regulate cardiac fibrosis.
  
  
  CONCLUSIONS
  Our present studies on the cardiac function of KLF6 show a new mechanism whereby cardiomyocytes regulate cardiac fibrosis through transcriptional control of the extracellular matrix factor, TSP4, which, in turn, modulates activation of cardiac fibroblasts.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Daigo
authors.initials: D
authors.lastname: Sawaki
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Lianguo
authors.initials: L
authors.lastname: Hou
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Tomida
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan The Key Laboratory of Biomedical Information Engineering, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Junqing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhan
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Jichi Medical University, Tochigi, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Aizawa
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Bo-Kyung
authors.initials: BK
authors.lastname: Son
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Kariya
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.affiliation: Cardiovascular Division, King's College London, London, UK.
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.affiliation: Program in Developmental Biology and Neonatal Medicine, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.affiliation: Division of Liver Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.affiliation: Jichi Medical University, Tochigi, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Jichi Medical University, Tochigi, Japan Department of Cardiovascular Sciences, University of Leicester, Leicester, UK National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK torusuzu-tky@umin.ac.jp ts263@le.ac.uk.
authors.forename: Toru
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: C491358:Klf6 protein, mouse; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D019699:Thrombospondins; D015534:Trans-Activators; C101864:thrombospondin 4
keywords: Angiotensin II; Cardiomyocyte; Fibrosis; Krüppel-like factor; Thrombospondin