High Mobility Group Box 1 (HMGB1) Mediates High-Glucose-Induced Calcification in Vascular Smooth Muscle Cells of Sapheno
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High Mobility Group Box 1 (HMGB1) Mediates High-GlucoseInduced Calcification in Vascular Smooth Muscle Cells of Saphenous Veins Yongyi Wang,1 Jianggui Shan,1 Wengang Yang,1 Hui Zheng,1 and Song Xue1,2
Abstract—Diabetes accelerates saphenous vein grafts calcification after years of coronary artery bypass grafting (CABG) surgery. Vascular smooth muscle cells (VSMC) undergoing a phenotypic switch to osteoblast-like cells play a key role in this process. The receptor for advanced glycation and products (RAGE) and toll-like receptors (TLRs) are all involved in various cardiovascular calcification processes. Therefore, the role of their common ligand, high mobility group box 1 (HMGB1), in high-glucose-induced calcification in VSMC of saphenous vein was investigated. In this study, VSMC were cultured from saphenous vein of patients arranged for CABG. We first demonstrated highglucose-induced HMGB1 translocation from nucleus to cytosol, and this translocation was induced through a NADPH oxidase and PKC-dependent pathway. We next found high glucose also increased TLR2, TLR4, and RAGE expression. Then, we revealed downregulating HMGB1 expression abolished high-glucose-induced calcification accompanied by NFκB inactivation and low expression of bone morphogenetic protein-2 (BMP-2). We further demonstrated NFκB activation was necessary in high-glucose-induced BMP-2 expression and calcification. Finally, by using a chromatin immunoprecipitation assay, we demonstrated NFκB transcriptional regulation of BMP-2 promoter was induced by NFκB binding to its κB element on the BMP-2 promoter. Our findings thus suggest HMGB1 plays an important role in mediating the calcification process induced by high glucose through NFκB activation and BMP-2 expression in VSMC of saphenous vein. KEY WORDS: saphenous vein graft; vascular smooth muscle cell; high glucose; calcification; high mobility group box 1.
INTRODUCTION Saphenous vein grafts (SVGs) are frequently used in coronary artery bypass grafting (CABG) surgery. After years of bypass surgery, atherosclerosis and calcification are the dominant disease processes, which cause late lumen loss of SVGs and subsequent ischemia for revascularization [1, 2]. Recently, a clinical study by using an intravascular ultrasound demonstrated calcium is located primarily in SVGs wall and not at the lesion plaque, and SVGs calcium
1
Department of Cardiovascular Surgery, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China 2 To whom correspondence should be addressed at Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, People’s Republic of China. E-mail: [email protected]
occurs more commonly in diabetic patients with insulin treatment [3]. Medial calcification is a common pathologic condition that occurs in diabetic patients, and may contribute to increased cardiovascular-related morality [4]. It was demonstrated vascular calcification is a consequence of tightly regulated processes that culminate in organiz
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