High Mobility Group Box 1 (HMGB1) Mediates High-Glucose-Induced Calcification in Vascular Smooth Muscle Cells of Saphenous Veins

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 high-glucose-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.