Zhan Jun-Kun, Wang Yan-Jiao, Wang Yi, Tang Zhi-Yong, Tan Pan, Huang Wu, Liu You-Shuo
Department of Geriatrics, Institute of Aging and Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China.
Department of Geriatrics, Institute of Aging and Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China.
Int J Cardiol. 2015 Jun 15;189:188-93. doi: 10.1016/j.ijcard.2015.04.086. Epub 2015 Apr 14.
Arterial calcification is a common event in cardiovascular pathogenesis. Osteoblastic differentiation of vascular smooth muscle cells (VSMCs) is the most important cytopathologic foundation of arterial calcification. Glucagon-like peptide-1 (GLP-1) exerts multiple cardioprotective actions beyond insulinotropic effects through GLP-1 receptor (GLP-1R). However, whether GLP-1 regulates osteoblastic differentiation of VSMCs and associated molecular mechanisms has not been clarified.
The human VSMC differentiation model was established by beta-glycerophosphate (β-GP) induction. The mineralization was measured by Alizarin Red S staining. Protein expression and phosphorylation were detected by Western blot or immunofluorescence. GLP-1R gene expression was silenced by siRNA.
The GLP-1 analogue liraglutide dose- and time-dependently inhibited the protein expression of osteoblastic differentiation markers alkaline phosphatase (ALP), osteocalcin (OC), and Runt-related transcription factor 2 (Runx2), phosphorylation of PI3K, Akt, mTOR, and S6K1. Silencing of GLP-1R gene expression by siRNA significantly blocked the effects of liraglutide in ALP protein expression and PI3K/Akt phosphorylation.
GLP-1 analogue liraglutide attenuates the osteoblastic differentiation and calcification of human VSMCs through its receptor and subsequent activation of PI3K/Akt/mTOR/S6K1 signaling. GLP-1 analogues may be potential agents for the treatment of cardiovascular diseases.
动脉钙化是心血管发病机制中的常见事件。血管平滑肌细胞（VSMC）向成骨细胞分化是动脉钙化最重要的细胞病理学基础。胰高血糖素样肽-1（GLP-1）通过GLP-1受体（GLP-1R）发挥多种心脏保护作用，而不仅仅是促胰岛素作用。然而，GLP-1是否调节VSMC的成骨细胞分化及其相关分子机制尚未阐明。
通过β-甘油磷酸酯（β-GP）诱导建立人VSMC分化模型。用茜素红S染色法检测矿化情况。通过蛋白质印迹或免疫荧光检测蛋白质表达和磷酸化情况。用小干扰RNA（siRNA）使GLP-1R基因表达沉默。
GLP-1类似物利拉鲁肽剂量和时间依赖性地抑制成骨细胞分化标志物碱性磷酸酶（ALP）、骨钙素（OC）和Runt相关转录因子2（Runx2）的蛋白质表达，以及PI3K、Akt、mTOR和S6K1的磷酸化。用siRNA使GLP-1R基因表达沉默显著阻断了利拉鲁肽对ALP蛋白质表达和PI3K/Akt磷酸化的影响。
GLP-1类似物利拉鲁肽通过其受体及随后激活PI3K/Akt/mTOR/S6K1信号通路减弱人VSMC的成骨细胞分化和钙化。GLP-1类似物可能是治疗心血管疾病的潜在药物。
