Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure

Akira Funayama, Tetsuro Shishido, Shunsuke Netsu, Taro Narumi, Shinpei Kadowaki, Hiroki Takahashi, Takuya Miyamoto, Tetsu Watanabe, Chang Hoon Woo, Jun-ichi Abe, Koichiro Kuwahara, Kazuwa Nakao, Yasuchika Takeishi, Isao Kubota

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

AimsHigh mobility group box 1 (HMGB1) is an abundant and ubiquitous nuclear DNA-binding protein that has multiple functions dependent on its cellular location. HMGB1 binds to DNA, facilitating numerous nuclear functions including maintenance of genome stability, transcription, and repair. However, little is known about the effects of nuclear HMGB1 on cardiac hypertrophy and heart failure. The aim of this study was to examine whether nuclear HMGB1 plays a role in the development of cardiac hypertrophy induced by pressure overload.Methods and resultsAnalysis of human biopsy samples by immunohistochemistry showed decreased nuclear HMGB1 expression in failing hearts compared with normal hearts. Nuclear HMGB1 decreased in response to both endothelin-1 (ET-1) and angiotensin II (Ang II) stimulation in neonatal rat cardiomyocytes, where nuclear HMGB1 was acetylated and translocated to the cytoplasm. Overexpression of nuclear HMGB1 attenuated ET-1 induced cardiomyocyte hypertrophy. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) and wild-type (WT) mice. Cardiac hypertrophy after TAC was attenuated in HMGB1-Tg mice and the survival rate after TAC was higher in HMGB1-Tg mice than in WT mice. Induction of foetal cardiac genes was decreased in HMGB1-Tg mice compared with WT mice. Nuclear HMGB1 expression was preserved in HMGB1-Tg mice compared with WT mice and significantly attenuated DNA damage after TAC was attenuated in HMGB1-TG mice.ConclusionThese results suggest that the maintenance of stable nuclear HMGB1 levels prevents hypertrophy and heart failure by inhibiting DNA damage.

Original languageEnglish (US)
Pages (from-to)657-664
Number of pages8
JournalCardiovascular Research
Volume99
Issue number4
DOIs
StatePublished - Sep 1 2013

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HMGB1 Protein
Cardiomegaly
Heart Failure
Constriction
Endothelin-1
Cardiac Myocytes
Hypertrophy
DNA Damage
Maintenance

Keywords

  • Acetylation
  • HMGB1
  • Heart failure
  • Pressure overload
  • Translocation

ASJC Scopus subject areas

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

Cite this

Funayama, A., Shishido, T., Netsu, S., Narumi, T., Kadowaki, S., Takahashi, H., ... Kubota, I. (2013). Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure. Cardiovascular Research, 99(4), 657-664. https://doi.org/10.1093/cvr/cvt128

Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure. / Funayama, Akira; Shishido, Tetsuro; Netsu, Shunsuke; Narumi, Taro; Kadowaki, Shinpei; Takahashi, Hiroki; Miyamoto, Takuya; Watanabe, Tetsu; Woo, Chang Hoon; Abe, Jun-ichi; Kuwahara, Koichiro; Nakao, Kazuwa; Takeishi, Yasuchika; Kubota, Isao.

In: Cardiovascular Research, Vol. 99, No. 4, 01.09.2013, p. 657-664.

Research output: Contribution to journalArticle

Funayama, A, Shishido, T, Netsu, S, Narumi, T, Kadowaki, S, Takahashi, H, Miyamoto, T, Watanabe, T, Woo, CH, Abe, J, Kuwahara, K, Nakao, K, Takeishi, Y & Kubota, I 2013, 'Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure', Cardiovascular Research, vol. 99, no. 4, pp. 657-664. https://doi.org/10.1093/cvr/cvt128
Funayama, Akira ; Shishido, Tetsuro ; Netsu, Shunsuke ; Narumi, Taro ; Kadowaki, Shinpei ; Takahashi, Hiroki ; Miyamoto, Takuya ; Watanabe, Tetsu ; Woo, Chang Hoon ; Abe, Jun-ichi ; Kuwahara, Koichiro ; Nakao, Kazuwa ; Takeishi, Yasuchika ; Kubota, Isao. / Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure. In: Cardiovascular Research. 2013 ; Vol. 99, No. 4. pp. 657-664.
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abstract = "AimsHigh mobility group box 1 (HMGB1) is an abundant and ubiquitous nuclear DNA-binding protein that has multiple functions dependent on its cellular location. HMGB1 binds to DNA, facilitating numerous nuclear functions including maintenance of genome stability, transcription, and repair. However, little is known about the effects of nuclear HMGB1 on cardiac hypertrophy and heart failure. The aim of this study was to examine whether nuclear HMGB1 plays a role in the development of cardiac hypertrophy induced by pressure overload.Methods and resultsAnalysis of human biopsy samples by immunohistochemistry showed decreased nuclear HMGB1 expression in failing hearts compared with normal hearts. Nuclear HMGB1 decreased in response to both endothelin-1 (ET-1) and angiotensin II (Ang II) stimulation in neonatal rat cardiomyocytes, where nuclear HMGB1 was acetylated and translocated to the cytoplasm. Overexpression of nuclear HMGB1 attenuated ET-1 induced cardiomyocyte hypertrophy. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) and wild-type (WT) mice. Cardiac hypertrophy after TAC was attenuated in HMGB1-Tg mice and the survival rate after TAC was higher in HMGB1-Tg mice than in WT mice. Induction of foetal cardiac genes was decreased in HMGB1-Tg mice compared with WT mice. Nuclear HMGB1 expression was preserved in HMGB1-Tg mice compared with WT mice and significantly attenuated DNA damage after TAC was attenuated in HMGB1-TG mice.ConclusionThese results suggest that the maintenance of stable nuclear HMGB1 levels prevents hypertrophy and heart failure by inhibiting DNA damage.",
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T1 - Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure

AU - Funayama, Akira

AU - Shishido, Tetsuro

AU - Netsu, Shunsuke

AU - Narumi, Taro

AU - Kadowaki, Shinpei

AU - Takahashi, Hiroki

AU - Miyamoto, Takuya

AU - Watanabe, Tetsu

AU - Woo, Chang Hoon

AU - Abe, Jun-ichi

AU - Kuwahara, Koichiro

AU - Nakao, Kazuwa

AU - Takeishi, Yasuchika

AU - Kubota, Isao

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N2 - AimsHigh mobility group box 1 (HMGB1) is an abundant and ubiquitous nuclear DNA-binding protein that has multiple functions dependent on its cellular location. HMGB1 binds to DNA, facilitating numerous nuclear functions including maintenance of genome stability, transcription, and repair. However, little is known about the effects of nuclear HMGB1 on cardiac hypertrophy and heart failure. The aim of this study was to examine whether nuclear HMGB1 plays a role in the development of cardiac hypertrophy induced by pressure overload.Methods and resultsAnalysis of human biopsy samples by immunohistochemistry showed decreased nuclear HMGB1 expression in failing hearts compared with normal hearts. Nuclear HMGB1 decreased in response to both endothelin-1 (ET-1) and angiotensin II (Ang II) stimulation in neonatal rat cardiomyocytes, where nuclear HMGB1 was acetylated and translocated to the cytoplasm. Overexpression of nuclear HMGB1 attenuated ET-1 induced cardiomyocyte hypertrophy. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) and wild-type (WT) mice. Cardiac hypertrophy after TAC was attenuated in HMGB1-Tg mice and the survival rate after TAC was higher in HMGB1-Tg mice than in WT mice. Induction of foetal cardiac genes was decreased in HMGB1-Tg mice compared with WT mice. Nuclear HMGB1 expression was preserved in HMGB1-Tg mice compared with WT mice and significantly attenuated DNA damage after TAC was attenuated in HMGB1-TG mice.ConclusionThese results suggest that the maintenance of stable nuclear HMGB1 levels prevents hypertrophy and heart failure by inhibiting DNA damage.

AB - AimsHigh mobility group box 1 (HMGB1) is an abundant and ubiquitous nuclear DNA-binding protein that has multiple functions dependent on its cellular location. HMGB1 binds to DNA, facilitating numerous nuclear functions including maintenance of genome stability, transcription, and repair. However, little is known about the effects of nuclear HMGB1 on cardiac hypertrophy and heart failure. The aim of this study was to examine whether nuclear HMGB1 plays a role in the development of cardiac hypertrophy induced by pressure overload.Methods and resultsAnalysis of human biopsy samples by immunohistochemistry showed decreased nuclear HMGB1 expression in failing hearts compared with normal hearts. Nuclear HMGB1 decreased in response to both endothelin-1 (ET-1) and angiotensin II (Ang II) stimulation in neonatal rat cardiomyocytes, where nuclear HMGB1 was acetylated and translocated to the cytoplasm. Overexpression of nuclear HMGB1 attenuated ET-1 induced cardiomyocyte hypertrophy. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) and wild-type (WT) mice. Cardiac hypertrophy after TAC was attenuated in HMGB1-Tg mice and the survival rate after TAC was higher in HMGB1-Tg mice than in WT mice. Induction of foetal cardiac genes was decreased in HMGB1-Tg mice compared with WT mice. Nuclear HMGB1 expression was preserved in HMGB1-Tg mice compared with WT mice and significantly attenuated DNA damage after TAC was attenuated in HMGB1-TG mice.ConclusionThese results suggest that the maintenance of stable nuclear HMGB1 levels prevents hypertrophy and heart failure by inhibiting DNA damage.

KW - Acetylation

KW - HMGB1

KW - Heart failure

KW - Pressure overload

KW - Translocation

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