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 Conway, Ichiro Manabe, Issei Komuro, Scott L. Friedman, Ryozo Nagai, Toru Suzuki

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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
Volume107
Issue number4
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

Cardiac Myocytes
Fibrosis
Fibroblasts
Knockout Mice
Extracellular Matrix
Kruppel-Like Transcription Factors
Microarray Analysis
Angiotensin II
Transcription Factors
Phenotype
Mutation
thrombospondin 4

Keywords

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

ASJC Scopus subject areas

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

Cite this

Modulation of cardiac fibrosis by Kru ppel-like factor 6 through transcriptional control of thrombospondin 4 in cardiomyocytes. / Sawaki, Daigo; Hou, Lianguo; Tomida, Shota; Sun, Junqing; Zhan, Hong; Aizawa, Kenichi; Kyung Son, Bo; Kariya, Taro; Takimoto, Eiki; Otsu, Kinya; Conway, Simon; Manabe, Ichiro; Komuro, Issei; Friedman, Scott L.; Nagai, Ryozo; Suzuki, Toru.

In: Cardiovascular Research, Vol. 107, No. 4, 2015, p. 420-430.

Research output: Contribution to journalArticle

Sawaki, D, Hou, L, Tomida, S, Sun, J, Zhan, H, Aizawa, K, Kyung Son, B, Kariya, T, Takimoto, E, Otsu, K, Conway, S, Manabe, I, Komuro, I, Friedman, SL, Nagai, R & Suzuki, T 2015, 'Modulation of cardiac fibrosis by Kru ppel-like factor 6 through transcriptional control of thrombospondin 4 in cardiomyocytes', Cardiovascular Research, vol. 107, no. 4, pp. 420-430. https://doi.org/10.1093/cvr/cvv155
Sawaki, Daigo ; Hou, Lianguo ; Tomida, Shota ; Sun, Junqing ; Zhan, Hong ; Aizawa, Kenichi ; Kyung Son, Bo ; Kariya, Taro ; Takimoto, Eiki ; Otsu, Kinya ; Conway, Simon ; Manabe, Ichiro ; Komuro, Issei ; Friedman, Scott L. ; Nagai, Ryozo ; Suzuki, Toru. / Modulation of cardiac fibrosis by Kru ppel-like factor 6 through transcriptional control of thrombospondin 4 in cardiomyocytes. In: Cardiovascular Research. 2015 ; Vol. 107, No. 4. pp. 420-430.
@article{b8f0a4f24f2d4fe9a75aac3cb72e61dd,
title = "Modulation of cardiac fibrosis by Kru ppel-like factor 6 through transcriptional control of thrombospondin 4 in cardiomyocytes",
abstract = "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.",
keywords = "Angiotensin II, Cardiomyocyte, Fibrosis, Kruppel-like factor, Thrombospondin",
author = "Daigo Sawaki and Lianguo Hou and Shota Tomida and Junqing Sun and Hong Zhan and Kenichi Aizawa and {Kyung Son}, Bo and Taro Kariya and Eiki Takimoto and Kinya Otsu and Simon Conway and Ichiro Manabe and Issei Komuro and Friedman, {Scott L.} and Ryozo Nagai and Toru Suzuki",
year = "2015",
doi = "10.1093/cvr/cvv155",
language = "English (US)",
volume = "107",
pages = "420--430",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "4",

}

TY - JOUR

T1 - Modulation of cardiac fibrosis by Kru ppel-like factor 6 through transcriptional control of thrombospondin 4 in cardiomyocytes

AU - Sawaki, Daigo

AU - Hou, Lianguo

AU - Tomida, Shota

AU - Sun, Junqing

AU - Zhan, Hong

AU - Aizawa, Kenichi

AU - Kyung Son, Bo

AU - Kariya, Taro

AU - Takimoto, Eiki

AU - Otsu, Kinya

AU - Conway, Simon

AU - Manabe, Ichiro

AU - Komuro, Issei

AU - Friedman, Scott L.

AU - Nagai, Ryozo

AU - Suzuki, Toru

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Angiotensin II

KW - Cardiomyocyte

KW - Fibrosis

KW - Kruppel-like factor

KW - Thrombospondin

UR - http://www.scopus.com/inward/record.url?scp=84948175046&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84948175046&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvv155

DO - 10.1093/cvr/cvv155

M3 - Article

C2 - 25987545

AN - SCOPUS:84948175046

VL - 107

SP - 420

EP - 430

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 4

ER -