Daigo Sawaki1, Lianguo Hou2, Shota Tomida1, Junqing Sun3, Hong Zhan1, Kenichi Aizawa4, Bo-Kyung Son1, Taro Kariya1, Eiki Takimoto1, Kinya Otsu5, Simon J Conway6, Ichiro Manabe1, Issei Komuro1, Scott L Friedman7, Ryozo Nagai8, Toru Suzuki9. 1. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 2. 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. 3. 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. 4. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Jichi Medical University, Tochigi, Japan. 5. Cardiovascular Division, King's College London, London, UK. 6. Program in Developmental Biology and Neonatal Medicine, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. 7. Division of Liver Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 8. Jichi Medical University, Tochigi, Japan. 9. 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.
Abstract
AIMS: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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