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

Title
Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure
Author(s)
Akira Funayama[Akira Funayama]Tetsuro Shishido[Tetsuro Shishido]Shunsuke Netsu[Shunsuke Netsu]Taro Narumi[Taro Narumi]Shinpei Kadowaki[Shinpei Kadowaki]Hiroki Takahashi[Hiroki Takahashi]Takuya Miyamoto[Takuya Miyamoto]Tetsu Watanabe[Tetsu Watanabe]우창훈Jun-ichi Abe[Jun-ichi Abe]Koichiro Kuwahara[Koichiro Kuwahara]Kazuwa Nakao[Kazuwa Nakao]Yasuchika Takeishi[Yasuchika Takeishi]Isao Kubota[Isao Kubota]
Keywords
CHROMATIN PROTEIN HMGB1; BASE-EXCISION-REPAIR; INFLAMMATORY RESPONSES; MYOCARDIAL-INFARCTION; REPERFUSION INJURY; DNA-DAMAGE; DYSFUNCTION; ACTIVATION; RELEASE; BINDING
Issue Date
201309
Publisher
OXFORD UNIV PRESS
Citation
CARDIOVASCULAR RESEARCH, v.99, no.4, pp.657 - 664
Abstract
High 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. Analysis 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. These results suggest that the maintenance of stable nuclear HMGB1 levels prevents hypertrophy and heart failure by inhibiting DNA damage.
URI
http://hdl.handle.net/YU.REPOSITORY/28968http://dx.doi.org/10.1093/cvr/cvt128
ISSN
0008-6363
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의과대학 > 약리학교실 > Articles
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