Activation of receptor for advanced glycation end products induces osteogenic differentiation of vascular smooth muscle cells.

AIM:Vascular calcification is prevalent in patients with diabetes and chronic kidney disease. Receptor for advanced glycation end products and its multiple ligands have been implicated in the pathogenesis of accelerated atherosclerosis; however, little is known about the effects of activation on vascular calcification. METHODS AND RESULTS:Cultured rat and human aortic smooth muscle cells (HASMC) were transduced with adenovirus expressing Expression of myocardin and the SMC-marker genes was significantly repressed in these cells. duanyu1648 activation inhibited myocardin-induced expression of the SMC genes in mouse embryonic mesenchymal C3H10T1/2 cells. Interestingly, duanyu1648 activation induced alkaline phosphatase (ALP) expression, calcium deposition, and Msx2 expression, a crucial transcription factor for osteogenic differentiation, in HASMC. osteogenic differentiation was significantly inhibited by endogenous secretory duanyu1648. duanyu1648-induced ALP and Msx2 expression was completely abrogated by DAPT, an inhibitor of the Notch signaling pathway. PD98059 (MEK inhibitor) effectively blunted duanyu1648-induced Notch1 and Msx2 gene expression. Simultaneous stimulation with bone morphogenetic protein 2 (BMP2) and duanyu1648 signaling synergistically induced expressions of Msx2 and ALP in HASMC. Immunohistochemistry revealed that the human calcifying atherosclerotic plaque expressed Notch components and Msx2. The ALP activity induced in HASMCs by human serum was positively correlated with the serum creatinine level, but not with phosphate and hemoglobin A1c levels. CONCLUSIONS:These results indicate that activation of duanyu1648 not only inhibits myocardin-dependent SMC gene expression, but also induces osteogenic differentiation of vascular SMC through Notch/Msx2 induction. These results provide a novel insight into the role of duanyu1648 axis in vascular calcification.

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