High-mobility group box 1 restores cardiac function after myocardial infarction in transgenic mice.
OBJECTIVE
High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein and is released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. To test the hypothesis that HMGB1 enhances angiogenesis and restores cardiac function after myocardial infarction (MI), we generated transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) using alpha-myosin heavy chain promoter.


RESULTS
The left anterior descending coronary artery was ligated in HMGB1-Tg and wild-type littermate (Wt) mice. After coronary artery ligation, HMGB1 was released into circulation from the necrotic cardiomyocytes of HMGB1-overexpressing hearts. The size of MI was smaller in HMGB1-Tg than in Wt mice. Echocardiography and cardiac catheterization demonstrated that cardiac remodelling and dysfunction after MI were prevented in HMGB1-Tg mice compared with Wt mice. Furthermore, the survival rate after MI of HMGB1-Tg mice was higher than that of Wt mice. Immunohistochemical staining revealed that capillary and arteriole formation after MI was enhanced in HMGB1-Tg mice.


CONCLUSIONS
We report the first in vivo evidence that HMGB1 enhances angiogenesis, restores cardiac function, and improves survival after MI. These results may provide a novel therapeutic approach for left ventricular dysfunction after MI.
Department of Cardiology, Pulmonology and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.
Tatsuro
T
Kitahara
Yasuchika
Y
Takeishi
Mutsuo
M
Harada
Takeshi
T
Niizeki
Satoshi
S
Suzuki
Toshiki
T
Sasaki
Mitsunori
M
Ishino
Olga
O
Bilim
Osamu
O
Nakajima
Isao
I
Kubota
D000818:Animals; D003331:Coronary Vessels / Q000254:growth & development*; D024243:HMGB1 Protein / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D008026:Ligation; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D018919:Neovascularization, Physiologic; D011401:Promoter Regions, Genetic; D024723:Ventricular Myosins / Q000235:genetics; D020257:Ventricular Remodeling
D024243:HMGB1 Protein; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains