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.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
Yiyu
Y
He
Xiaoya
X
Zhou
Xiaoxin
X
Zheng
Xuejun
X
Jiang
D000818:Animals; D015153:Blotting, Western; D024243:HMGB1 Protein / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects*
D024243:HMGB1 Protein; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta