Loss of endogenous HMGB2 promotes cardiac dysfunction and pressure overload-induced heart failure in mice

Michio Sato, Keishi Miyata, Zhe Tian, Tsuyoshi Kadomatsu, Yoshihiro Ujihara, Jun Morinaga, Haruki Horiguchi, Motoyoshi Endo, Jiabin Zhao, Shunshun Zhu, Taichi Sugizaki, Kimihiro Igata, Masashi Muramatsu, Takashi Minami, Takashi Ito, Marco E. Bianchi, Satoshi Mohri, Kimi Araki, Koichi Node, Yuichi Oike

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The rapid increase in the number of heart failure (HF) patients in parallel with the increase in the number of older people is receiving attention worldwide. HF not only increases mortality but decreases quality of life, creating medical and social problems. Thus, it is necessary to define molecular mechanisms underlying HF development and progression. HMGB2 is a member of the high-mobility group superfamily characterized as nuclear proteins that bind DNA to stabilize nucleosomes and promote transcription. A recent in vitro study revealed that HMGB2 loss in cardiomyocytes causes hypertrophy and increases HF-associated gene expression. However, it’s in vivo function in the heart has not been assessed. Methods and Results: Western blotting analysis revealed increased HMGB2 expression in heart tissues undergoing pressure overload by transverse aorta constriction (TAC) in mice. Hmgb2 homozygous knockout (Hmgb2 -/- ) mice showed cardiac dysfunction due to AKT inactivation and decreased sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA)2a activity. Compared to wild-type mice, Hmgb2 -/- mice had worsened cardiac dysfunction after TAC surgery, predisposing mice to HF development and progression. Conclusions: This study demonstrates that upregulation of cardiac HMGB2 is an adaptive response to cardiac stress, and that loss of this response could accelerate cardiac dysfunction, suggesting that HMGB2 plays a cardioprotective role.

Original languageEnglish
Pages (from-to)368-378
Number of pages11
JournalCirculation Journal
Volume83
Issue number2
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Aging
  • Heart failure
  • HMGB2
  • Transverse aorta constriction (TAC) model

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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