Exenatide can inhibit calcification of human VSMCs through the NF-kappaB/RANKL signaling pathway

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.

Nonglycemic effects of incretins in patients with long-term type 1 diabetes mellitus and chronic kidney disease

“…В работе Jun-Kun Zhan и соавт. [23] изучалось влияние агониста рецептора ГПП-1 на па-тогенетические звенья, лежащие в основе кальцификации сосудистой стенки. Исследование показало, что агонист рецептора ГПП-1 обладает зависимым от дозы ингибиру-ющим влиянием на активность β-глицеролфосфата, по-тенцирующего дифференциацию остеобластов и кальци-фикацию сосудистых ГМК, а также лиганда-рецептора активатора ядерного фактора каппа-В (Receptor Activator of NF-κB Ligand-RANKL), являющегося мощным стиму-лятором минерализации сосудистых ГМК [23].…”

“…[23] изучалось влияние агониста рецептора ГПП-1 на па-тогенетические звенья, лежащие в основе кальцификации сосудистой стенки. Исследование показало, что агонист рецептора ГПП-1 обладает зависимым от дозы ингибиру-ющим влиянием на активность β-глицеролфосфата, по-тенцирующего дифференциацию остеобластов и кальци-фикацию сосудистых ГМК, а также лиганда-рецептора активатора ядерного фактора каппа-В (Receptor Activator of NF-κB Ligand-RANKL), являющегося мощным стиму-лятором минерализации сосудистых ГМК [23]. Исследо-вательские работы в данном направлении продолжаются, но и в настоящее время имеющиеся данные указывают на широкий терапевтический потенциал и разнообразие благоприятных эффектов агонистов рецептора ГПП-1, что, возможно, будет способствовать пополнению списка показаний к применению препаратов этой группы.…”

Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists

“…Osteocalcin concentration significantly increases during calcification and arterial calcification is an important complication of diabetes due to the differentiation of vascular smooth muscle cells into osteoblast-like cells. Although some work demonstrates an inhibitory effect of GLP-1RAs on vascular calcifications, this is not always the case (Zhan et al 2014, Davenport et al 2015.…”

Melatonin alleviates vascular calcification and ageing through exosomal miR‐204/miR‐211 cluster in a paracrine manner

“…5 Vascular calcification and other dysfunctions of the middle vascular membrane are closely related to VSMC phenotypic conversion, transdifferentiation and apoptosis. 6,7 Some studies have demonstrated that exosomes play an important role in angiogenesis, vascular calcification and senescence of VSMCs. [8][9][10][11] By transferring information among cells, exosomes in cellular senescence processes can regulate cell-cell communication.…”