High-mobility group box 1 restores cardiac function after myocardial infarction in transgenic mice

Aim: 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, we generated transgenic mice with cardiac specific overexpression of HMGB1 (HMGB1-Tg) using α-myosin heavy chain (MHC) promoter. Methods and 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 myocardial infarction was smaller in HMGB1-Tg than in Wt mice. Echocardiography and cardiac catheterization demonstrated that cardiac remodeling and dysfunction after myocardial infarction were prevented in HMGB1-Tg mice compared to Wt mice. Furthermore, survival rate after myocardial infarction of HMGB1-Tg mice was higher than that of Wt mice. Immunohistochemical staining revealed that capillary and arteriole formations after myocardial infarction were enhanced in HMGB1-Tg mice. Conclusions: We demonstrated the first in vivo evidence that HMGB1 enhances angiogenesis, restores cardiac function, and improves survival after myocardial infarction. These results may provide a novel therapeutic approach for left ventricular dysfunction after myocardial infarction