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Krüppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling

Nature Medicine volume 8, pages 856–863 (2002)Cite this article

Abstract

We recently isolated a Krüppel-like zinc-finger transcription factor 5 (KLF5; also known as BTEB2 and IKLF), which is markedly induced in activated vascular smooth-muscle cells and fibroblasts. Here we describe our analysis of the in vivo function of KLF5 using heterozygous KLF5-knockout mice (Klf5+/−). In response to external stress, Klf5+/− mice showed diminished levels of arterial-wall thickening, angiogenesis, cardiac hypertrophy and interstitial fibrosis. Also, angiotensin II induced expression of KLF5, which in turn activated platelet-derived growth factor-A (PDGF-A) and transforming growth factor-β (TGF-β) expression. In addition, we determined that KLF5 interacted with the retinoic-acid receptor (RAR), that synthetic RAR ligands modulated KLF5 transcriptional activity, and that in vivo administration of RAR ligands affected stress responses in the cardiovascular system in a KLF5-dependent manner. KLF5 thus seems to be a key element linking external stress and cardiovascular remodeling.

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Figure 1: Targeted disruption of mouse Klf5.
Figure 2: Reduced vascular remodeling and angiogenesis in Klf5+/− mice.
Figure 3: Reduced angiotensin II-induced cardiac hypertrophy and fibrosis in Klf5+/− mice.
Figure 4: Transcriptional control of pdgfa by KLF5
Figure 5: Reduced growth factor expression in Klf5+/− mice
Figure 6: Effects of retinoids on KLF5 activity

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Acknowledgements

We thank T. Collins for the PDGF-A reporter constructs, CT. Teng for the human IKLF construct; SF. Yet for the GKLF construct; R. Urrutia for the TIEG construct; and H. Kumagaya for the S180 cell line. This study was supported in part by a Grant-in-Aid for Millennium Projects from the Ministry of Health, Labor and Welfare, Japan and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan

    Takayuki Shindo, Ichiro Manabe, Kenichi Aizawa, Saku Miyamoto, Yasushi Imai, Toru Suzuki, Hiroyuki Morita, Koji Maemura, Masataka Sata, Yasunobu Hirata & Ryozo Nagai

  2. Department of Gastroenterology, University of Tokyo, Tokyo, Japan

    Yasushi Fukushima & Takashi Ishikawa

  3. Department of Metabolic Diseases, University of Tokyo, Tokyo, Japan

    Kazuyuki Tobe & Takashi Kadowaki

  4. Department of Urology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Nobuo Moriyama & Hiroaki Nishimatsu

  5. Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

    Hiroyuki Kagechika

  6. Second Department of Internal Medicine, Gunma University School of Medicine, Gunma, Japan

    Keiko Kawai-Kowase & Masahiko Kurabayashi

  7. Department of Anatomy, Kyorin University, Tokyo, Japan

    Hayato Kawakami

  8. Institute of Medicinal Molecular Design, Inc., Tokyo, Japan

    Masayuki Komukai

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  1. Takayuki Shindo
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Correspondence to Ryozo Nagai.

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Shindo, T., Manabe, I., Fukushima, Y. et al. Krüppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling. Nat Med 8, 856–863 (2002). https://doi.org/10.1038/nm738

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