Association of Serum HMGB2 Levels With In-Stent Restenosis: HMGB2 Promotes Neointimal Hyperplasia in Mice With Femoral Artery Injury and Proliferation and Migration of VSMCs.
In a previous study, we established diabetic and nondiabetic minipig models with coronary artery in-stent restenosis (ISR). Mass spectrometry showed that high-mobility group box (HMGB) 2 level was higher in ISR than in non-ISR tissue from diabetic minipigs. We here investigated whether serum HMGB2 levels were related to ISR in coronary artery disease patients. The effect of HMGB2 was evaluated in mice with femoral artery wire injury and in human aortic smooth muscle cells.



From 2513 patients undergoing coronary artery intervention and follow-up angiography at ≈1 year, 262 patients were diagnosed with ISR, and 298 patients with no ISR were randomly included as controls. Serum HMGB2 levels were significantly higher in patients with ISR than in those without ISR and were associated with ISR severity. Multivariable logistic regression analysis showed that HMGB2 level was independently associated with ISR. In experiments, HMGB2 expression was increased in vascular tissue after injury. Perivascular HMGB2 administration promoted injury-induced neointimal hyperplasia in C57Bl/6 mice compared with in the control, whereas such pathophysiological features were attenuated inHmgb2-/-mice. Mechanistically, HMGB2 enhanced neointimal hyperplasia in mice and proliferation and migration in human aortic smooth muscle cells by inducing reactive oxygen species through increased p47phox phosphorylation. Knocking down p47phox, however, inhibited HMGB2-induced effects in human aortic smooth muscle cells. Finally, HMGB2-induced effects were significantly declined in receptor of advanced glycation end products knockdown or deficient cells, but not in Toll-like receptor 4 knockdown or deficient cells.



Serum HMGB2 levels were associated with ISR in patients. HMGB2 promoted neointimal hyperplasia in mice with arterial wire injury through reactive oxygen species activation.
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Yu Hu
YH
He
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Xiao Qun
XQ
Wang
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Jian
J
Zhang
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Zhu Hui
ZH
Liu
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Wen Qi
WQ
Pan
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Ying
Y
Shen
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Zheng Bin
ZB
Zhu
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Ling Jie
LJ
Wang
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Xiao Xiang
XX
Yan
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Ke
K
Yang
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Rui Yan
RY
Zhang
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Wei Feng
WF
Shen
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.).
Feng Hua
FH
Ding
From the Department of Cardiology, Rui Jin Hospital (Y.H.H., X.Q.W., Z.H.L., W.Q.P., Y.S., Z.B.Z., L.J.W., X.X.Y., R.Y.Z., W.F.S., F.H.D., L.L.) and Institute of Cardiovascular Diseases (Y.H.H., X.Q.W., Z.H.L., L.J.W., X.X.Y., K.Y., W.F.S., L.L.), Shanghai Jiaotong University School of Medicine, China; and Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China (J.Z.) rjlulin1965@163.com ruijindfh@126.com.
Lin
L
Lu
D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood / Q000000981:diagnostic imaging / Q000628:therapy*; D023903:Coronary Restenosis / Q000097:blood / Q000000981:diagnostic imaging / Q000209:etiology*; D004195:Disease Models, Animal; D005260:Female; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D024261:HMGB2 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia; D016015:Logistic Models; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D015999:Multivariate Analysis; D009131:Muscle, Smooth, Vascular / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D058426:Neointima; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects* / Q000295:instrumentation; D010641:Phenotype; D010766:Phosphorylation; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D015607:Stents; D013552:Swine; D013556:Swine, Miniature; D014162:Transfection; D057772:Vascular System Injuries / Q000097:blood* / Q000235:genetics / Q000473:pathology
C000593871:AGER protein, human; D015415:Biomarkers; D024261:HMGB2 Protein; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1
HMGB2; ROS; in-stent restenosis; neointimal hyperplasia; p47phox