• Yu Hu He, Xiao Qun Wang, Jian Zhang, Zhu Hui Liu, Wen Qi Pan, Ying Shen, Zheng Bin Zhu, Ling Jie Wang, Xiao Xiang Yan, Ke Yang, Rui Yan Zhang, Wei Feng Shen, Feng Hua Ding, and Lin Lu.
• 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.).
• Arterioscler. Thromb. Vasc. Biol. 2017 Apr 1; 37 (4): 717-729.

ObjectiveIn 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.Approach And ResultsFrom 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 in Hmgb2-/- 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.ConclusionsSerum HMGB2 levels were associated with ISR in patients. HMGB2 promoted neointimal hyperplasia in mice with arterial wire injury through reactive oxygen species activation.© 2017 American Heart Association, Inc.

73 keywords...

hide…