Modulation of cardiac fibrosis by Kru ppel-like factor 6 through transcriptional control of thrombospondin 4 in cardiomyocytes

Daigo Sawaki, Lianguo Hou, Shota Tomida, Junqing Sun, Hong Zhan, Kenichi Aizawa, Bo Kyung Son, Taro Kariya, Eiki Takimoto, Kinya Otsu, Simon J. Conway, Ichiro Manabe, Issei Komuro, Scott L. Friedman, Ryozo Nagai, Toru Suzuki

Research output: Contribution to journalArticlepeer-review


Kruppel-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.

Original languageEnglish (US)
Pages (from-to)420-430
Number of pages11
JournalCardiovascular Research
Issue number4
StatePublished - 2015
Externally publishedYes


  • Angiotensin II
  • Cardiomyocyte
  • Fibrosis
  • Kruppel-like factor
  • Thrombospondin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology


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