Abstract
BackgroundArterial calcification is an important pathological change of diabetic vascular complication. Osteoblastic differentiation of vascular smooth muscle cells (VSMCs) plays an important cytopathologic role in arterial calcification. The glucagon-like peptide-1 receptor agonists (GLP-1RA), a novel type of antidiabetic drugs, exert cardioprotective effects through the GLP-1 receptor (GLP-1R). However, the question of whether or not GLP-1RA regulates osteoblastic differentiation and calcification of VSMCs has not been answered, and the associated molecular mechanisms have not been examined.MethodsCalcifying VSMCs (CVSMCs) were isolated from cultured human arterial smooth muscle cells through limiting dilution and cloning. The extent of matrix mineralization was measured by Alizarin Red S staining. Protein expression and phosphorylation were detected by Western blot. Gene expression of receptor activator of nuclear factor-κB ligand (RANKL) was silenced by small interference RNA (siRNA).ResultsExenatide, an agonist of GLP-1 receptor, attenuated β-glycerol phosphate (β-GP) induced osteoblastic differentiation and calcification of human CVSMCs in a dose- and time-dependent manner. RANKL siRNA also inhibited osteoblastic differentiation and calcification. Exenatide decreased the expression of RANKL in a dose-dependent manner. 1,25 vitD3 (an activator of RANKL) upregulated, whereas BAY11-7082 (an inhibitor of NF-κB) downregulated RANKL, alkaline phosphatase (ALP), osteocalcin (OC), and core binding factor α1 (Runx2) protein levels and reduced mineralization in human CVSMCs. Exenatide decreased p-NF-κB and increased p-AMPKα levels in human CVSMCs 48 h after treatment. Significant decrease in p-NF-κB (p-Ser276, p-Ser536) level was observed in cells treated with exenatide or exenatide + BAY11-7082.ConclusionGLP-1RA exenatide can inhibit human VSMCs calcification through NF-κB/RANKL signaling.
Highlights
Diabetes mellitus is a major risk factor for the development of cardiovascular disease [1]
Effects of exenatide and Receptor activator of nuclear factor-κB ligand (RANKL)-small interference RNA (siRNA) on osteoblastic differentiation and calcification of human Calcifying vascular smooth muscle cell (VSMC) (CVSMCs) To determine the effect of glucagon-like peptide-1 receptor agonists (GLP-1RA) and RANKL on the osteoblastic differentiation and calcification of human CVSMCs, a GLP-1 receptor agonist and RANKL siRNA were used
Treatment with siRNARANKL blocked the expression of RANKL protein in human CVSMCs
Summary
Diabetes mellitus is a major risk factor for the development of cardiovascular disease [1]. Treatment of diabetes and its cardiovascular complications with classic drugs is effective in less than 50% of patients [2]. Novel therapies are required to manage diabetes mellitus and mitigate cardiovascular risks. Arterial calcification is an important pathological change of diabetic vascular complication. Osteoblastic differentiation of vascular smooth muscle cells (VSMCs) plays an important cytopathologic role in arterial calcification. The glucagon-like peptide-1 receptor agonists (GLP-1RA), a novel type of antidiabetic drugs, exert cardioprotective effects through the GLP-1 receptor (GLP-1R). The question of whether or not GLP-1RA regulates osteoblastic differentiation and calcification of VSMCs has not been answered, and the associated molecular mechanisms have not been examined
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