Inhibition of high-mobility group box 1 improves myocardial fibrosis and dysfunction in diabetic cardiomyopathy.
BACKGROUND
High-mobility group box 1 (HMGB1) is an important mediator of the inflammatory response. Its expression is increased in diabetic cardiomyopathy (DCM), but its role is unclear. We investigated the potential role and mechanism of HMGB1 in diabetes-induced myocardial fibrosis and dysfunction in mice.


METHODS
In vivo, type 1 diabetes was induced by streptozotocin (STZ) in mice. HMGB1 expression was knocked down by lentivirus-mediated short-hairpin RNA (shRNA). Cardiac function was assessed by echocardiography. Total collagen deposition was assessed by Masson's trichrome and Picrosirius red staining. HMGB1, collagen I and III, and transforming growth factor β1 (TGF-β1) expression was quantified by immunostaining and western bolt analysis. In vitro, isolated neonatal cardiac fibroblasts were treated with high glucose (HG) or recombinant HMGB1 (rHMGB1). Pharmacologic (neutralizing anti-HMGB1 antibody) or genetic (shRNA-HMGB1) inhibition of HMGB1 was used to investigate the role of HMGB1 in HG-induced functional changes of cardiac fibroblasts.


RESULTS
In vivo, HMGB1 was diffusely expressed in the myocardium of diabetic mice. HMGB1 silencing ameliorated left ventricular dysfunction and remodeling and decreased collagen deposition in diabetic mice. In vitro, HG induced HMGB1 translocation and secretion in both viable cardiomyocytes and fibroblasts. Administration of rHMGB1 dose-dependently increased the expression of collagens I and III and TGF-β1 in cardiac fibroblasts. HMGB1 inhibition reduced HG-induced collagen production, matrix metalloproteinase (MMP) activities, proliferation, and activated mitogen-activated protein kinase signaling in cardiac fibroblasts.


CONCLUSIONS
HMGB1 inhibition could alleviate cardiac fibrosis and remodeling in diabetic cardiomyopathy. Inhibition of HMGB1 might have therapeutic potential in the treatment of the disease.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health,Qilu Hospital of Shandong University, Jinan, Shandong, China.
Wen-Ke
WK
Wang
Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Ben
B
Wang
Department of Cardiology, The Second Hospital of Shandong University, Jinan, China.
Qing-Hua
QH
Lu
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health,Qilu Hospital of Shandong University, Jinan, Shandong, China.
Wei
W
Zhang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health,Qilu Hospital of Shandong University, Jinan, Shandong, China.
Wei-Dong
WD
Qin
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health,Qilu Hospital of Shandong University, Jinan, Shandong, China.
Xiang-Juan
XJ
Liu
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health,Qilu Hospital of Shandong University, Jinan, Shandong, China.
Xiao-Qian
XQ
Liu
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health,Qilu Hospital of Shandong University, Jinan, Shandong, China.
Feng-Shuang
FS
An
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health,Qilu Hospital of Shandong University, Jinan, Shandong, China. Electronic address: zhangyun@sdu.edu.cn.
Yun
Y
Zhang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health,Qilu Hospital of Shandong University, Jinan, Shandong, China. Electronic address: zhangmingxiang@sdu.edu.cn.
Ming-Xiang
MX
Zhang
D000818:Animals; D018929:Cell Culture Techniques; D002465:Cell Movement; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D005355:Fibrosis / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism; D024243:HMGB1 Protein / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000276:immunology; D032383:Myocytes, Cardiac / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology
D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D034741:RNA, Small Interfering; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
Cardiac fibroblasts; Diabetic cardiomyopathy; Fibrosis; High-mobility group box 1