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HMGB1 mediates hyperglycaemia-induced cardiomyocyte apoptosis via ERK/Ets-1 signalling pathway

Wen-Ke Wang1, Qing-Hua Lu, Jia-Ning Zhang

  • 1The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.

Journal of Cellular and Molecular Medicine
|September 12, 2014
PubMed

Insights

High mobility group box 1 protein (HMGB1) inhibition protects against high glucose-induced cardiomyocyte apoptosis. HMGB1 reduction decreases cell death by down-regulating extracellular signal-regulated kinase (ERK) and Ets-1 signaling pathways.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Diabetology

Background:

  • Diabetic cardiomyopathy involves cardiomyocyte apoptosis.
  • High mobility group box 1 protein (HMGB1) expression increases in diabetic conditions.
  • The mechanism of high glucose (HG)-induced cardiomyocyte apoptosis is not fully understood.

Purpose of the Study:

  • To investigate the role of HMGB1 in high glucose (HG)-induced cardiomyocyte apoptosis.
  • To elucidate the molecular mechanism underlying HG-induced cardiomyocyte apoptosis.

Main Methods:

  • Primary cardiomyocytes were treated with HG and HMGB1 was inhibited using short-hairpin RNA.
  • Caspase-3 activation and the ratio of Bcl2-associated X protein to B-cell lymphoma/leukemia-2 (bax/bcl-2) were measured.
  • Extracellular signal-regulated kinase 1/2 (ERK1/2) and Ets-1 activation were assessed in vitro and in vivo using streptozotocin-induced diabetic mice.

Main Results:

  • HG treatment increased cardiomyocyte apoptosis and HMGB1 levels.
  • HMGB1 inhibition reduced HG-induced apoptosis by decreasing caspase-3 activation and altering the bax/bcl-2 ratio.
  • HMGB1 inhibition attenuated HG-induced activation of Ets-1 via the ERK1/2 pathway.
  • Inhibition of Ets-1 also decreased HG-induced cardiomyocyte apoptosis.
  • Similar protective effects of HMGB1 inhibition were observed in diabetic mice, reducing myocardial apoptosis and ERK/Ets-1 activation.

Conclusions:

  • HMGB1 plays a critical role in high glucose-induced cardiomyocyte apoptosis.
  • Inhibition of HMGB1 may offer a therapeutic strategy against hyperglycaemia-induced cardiac damage.
  • The protective mechanism involves the down-regulation of ERK-dependent Ets-1 activation.

Keywords:
Ets-1HMGB1apoptosiscardiomyocytediabeteshigh glucose

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