Exenatide can inhibit calcification of human VSMCs through the NF-kappaB/RANKL signaling pathway.
Exenatide can inhibit calcification of human VSMCs through the NF-kappaB/RANKL signaling pathway.
复制标题
艾塞那肽可以通过 NF-kappaB/RANKL 信号通路抑制人 VSMC 的钙化。
DOI：
10.1186/s12933-014-0153-4
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发表时间：
2014-11-19
影响因子：
9.3
通讯作者：
Liu YS
中科院分区：
文献类型：
--
作者：
Zhan JK;Tan P;Wang YJ;Wang Y;He JY;Tang ZY;Huang W;Liu YS
动脉钙化是糖尿病血管并发症的重要病理改变。血管平滑肌细胞（VSMCs）的成骨分化在动脉钙化中起着重要的细胞病理学作用。胰高血糖素样肽-1受体激动剂（GLP-1 RA）是一种新型的抗糖尿病药物，通过GLP-1受体（GLP-1 R）发挥心脏保护作用。然而，GLP-1 RA是否调节VSMC的成骨细胞分化和钙化的问题尚未得到回答，相关的分子机制尚未得到研究。通过有限稀释和克隆的方法从培养的人动脉平滑肌细胞中分离出钙化的VSMCs（CVSMCs）。茜素红S染色测定基质矿化程度。Western blot检测蛋白表达和磷酸化水平。用小干扰RNA（siRNA）沉默核因子-κB配体受体激活因子（RANKL）的基因表达。艾塞那肽是一种GLP-1受体激动剂，以剂量和时间依赖性方式减弱β-磷酸甘油（β-GP）诱导的人CVSMC成骨分化和钙化。RANKL siRNA还抑制成骨细胞分化和钙化。艾塞那肽以剂量依赖性方式降低RANKL的表达。1，25 vitD 3（RANKL的激活剂）上调，而BAY 11 -7082（NF-κB的抑制剂）下调RANKL、碱性磷酸酶（ALP）、骨钙素（OC）和核心结合因子α1（Runx 2）蛋白水平，并减少人CVSMC中的矿化。在处理后48 h，艾塞那肽降低人CVSMC中的p-NF-κB水平并增加p-AMPKα水平。在用艾塞那肽或艾塞那肽+BAY 11 -7082处理的细胞中观察到p-NF-κB（p-Ser 276，p-Ser 536）水平显著降低。GLP-1 RA外激动剂可通过NF-κB/RANKL信号通路抑制人VSMCs钙化。
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). 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. Calcifying 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). Exenatide, 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. GLP-1RA exenatide can inhibit human VSMCs calcification through NF-κB/RANKL signaling.
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通讯作者：
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