High-mobility group box 1-mediated heat shock protein beta 1 expression attenuates mitochondrial dysfunction and apoptosis.
OBJECTIVE
Apoptosis of cardiomyocytes is thought to account for doxorubicin cardiotoxicity as it contributes to loss of myocardial tissue and contractile dysfunction. Given that high-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein capable of inhibiting apoptosis, we aimed to clarify the role of HMGB1 in heat shock protein beta 1 (HSPB1) expression during doxorubicin-induced cardiomyopathy.


RESULTS
Mitochondrial damage, cardiomyocyte apoptosis, and cardiac dysfunction after doxorubicin administration were significantly attenuated in mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) compared with wild type (WT) -mice. HSPB1 levels after doxorubicin administration were significantly higher in HMGB1-Tg mice than in WT mice. Transfection with HMGB1 increased the expression of HSPB1 at both the protein and mRNA levels, and HMGB1 inhibited mitochondrial dysfunction and apoptosis after exposure of cardiomyocytes to doxorubicin. HSPB1 silencing abrogated the inhibitory effect of HMGB1 on cardiomyocyte apoptosis. Doxorubicin increased the binding of HMGB1 to heat shock factor 2 and enhanced heat shock element promoter activity. Moreover, HMGB1 overexpression greatly enhanced heat shock element promoter activity. Silencing of heat shock factor 2 attenuated HMGB1-dependent HSPB1 expression and abrogated the ability of HMGB1 to suppress cleaved caspase-3 accumulation after doxorubicin stimulation.


CONCLUSIONS
We report the first in vivo and in vitro evidence that cardiac HMGB1 increases HSPB1 expression and attenuates cardiomyocyte apoptosis associated with doxorubicin-induced cardiomyopathy. Cardiac HMGB1 increases HSPB1 expression in cardiomyocytes in a heat shock factor 2-dependent manner.
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Taro
T
Narumi
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan. Electronic address: tshishid@med.id.yamagata-u.ac.jp.
Tetsuro
T
Shishido
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Yoichiro
Y
Otaki
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Shinpei
S
Kadowaki
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Yuki
Y
Honda
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Akira
A
Funayama
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Shintaro
S
Honda
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Hiromasa
H
Hasegawa
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Daisuke
D
Kinoshita
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Miyuki
M
Yokoyama
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Satoshi
S
Nishiyama
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Hiroki
H
Takahashi
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Takanori
T
Arimoto
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Takuya
T
Miyamoto
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Tetsu
T
Watanabe
Research Institute for Medical Sciences, Yamagata University School of Medicine, Yamagata, Japan.
Atsushi
A
Tanaka
Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
Chang-Hoon
CH
Woo
Department of Cardiology Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jun-ichi
J
Abe
Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
Yasuchika
Y
Takeishi
Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Isao
I
Kubota
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D002460:Cell Line; D002478:Cells, Cultured; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011401:Promoter Regions, Genetic; D051381:Rats; D015533:Transcriptional Activation
D024243:HMGB1 Protein; D055551:HSP27 Heat-Shock Proteins; D004317:Doxorubicin
Apoptosis; Cardiomyopathy; Heart failure; Mitochondria; Molecular biology