Exogenous high‐mobility group box 1 protein prevents postinfarction adverse myocardial remodeling through TGF‐β/Smad signaling pathway

High‐mobility group box 1 (HMGB1) has been reported to attenuate ventricular remodeling, but its mechanism remains mostly unresolved. Transforming growth factor‐beta (TGF‐β) is a crucial mediator in the pathogenesis of post‐infarction remodeling. Our study focused on the effects of HMGB1 on ventricular remodeling, and explored whether or not these effects were depended upon the TGF‐β signaling pathway. Rats underwent coronary artery ligation. An intramyocardium injection of phosphate buffered saline (PBS) with or without HMGB1 was administered 3 weeks after myocardial infarction (MI). At 4 weeks after the treatment, HMGB1 significantly increased the left ventricular ejection fraction (LVEF) (P < 0.05), decreased the left ventricular end diastolic dimension (LVEDD; P < 0.05), left ventricular end systolic dimension (LVESD) (P < 0.05) and the infarct size (P < 0.05) compared with control group. The expressions of collagen I, collagen III, and tissue inhibitor of metalloproteinase 2 (TIMP2) were also decreased, while the matrix metalloproteinases 2 (MMP2) and MMP9 expressions were upregulated by HMGB1 injection (P < 0.05) compared with control group. No effect on TIMP3 was observed. Furthermore, TGF‐β1 and phosphor‐Smad2 (p‐Smad2) were significantly suppressed and Smad7 was increased in HMGB1‐treated group (P < 0.05) compared with control group, no effects on p‐Smad3 and p‐p38 were observed. HMGB1 also upregulated Smad 7 expression and decreased the level of collagen I on cardiac fibroblasts (P < 0.05). Silencing of Smad7 gene by small interfering RNA abolished the fibrogenic effects of HMGB1 on cardiac fibroblasts (P < 0.05). These finding suggested that HMGB1 injection modulated ventricular remodeling may function through the possible inhibition of TGF‐β/Smad signaling pathway. J. Cell. Biochem. 114: 1634–1641, 2013. © 2013 Wiley Periodicals, Inc.