Inhibition of osteo/chondrogenic transformation of vascular smoothmuscle cells by MgCl2 via calcium-sensing receptor
Inhibition of osteo/chondrogenic transformation of vascular smoothmuscle cells by MgCl2 via calcium-sensing receptor
复制标题
DOI：
10.1097/hjh.0000000000001202
复制
发表时间：
2017-03-01
影响因子：
4.9
通讯作者：
Voelkl, Jakob
中科院分区：
文献类型：
--
作者：
Alesutan, Ioana;Tuffaha, Rashad;Voelkl, Jakob
目的：血管钙化的进展是一个由血管平滑肌细胞（VSMCs）的骨/软骨转化促进的活跃过程，通过钙感应受体（CASR）的激活而减弱。最近的体外研究表明，Mg2+可以钝化血管钙化，但其潜在机制尚不清楚。本研究探讨了MgCl2对血管钙化的影响是否涉及CASR。方法：采用人主动脉平滑肌细胞（HAoSMCs）和维生素D-3超载小鼠血管钙化模型进行实验。结果：磷酸盐诱导的钙沉积和成骨标志物msh homobox 2 （MSX2）、CBFA1（核心结合因子a1）和ALPL（组织非特异性碱性磷酸酶）的mRNA表达在MgCl2的额外处理下被钝化。MgCl2以剂量依赖的方式上调HAoSMCs中CASR mRNA的表达。此外，MgCl2对磷酸盐诱导的钙沉积和成骨标志物mRNA表达的抑制作用由CASR激动剂GdCl3模拟，并通过CASR拮抗剂NPS-2143或沉默CASR基因在HAoSMCs中逆转。MgCl2对羟基磷灰石颗粒诱导的VSMCs的成骨转化也有钝化作用。高剂量胆骨化醇可诱导小鼠血管钙化，上调主动脉成骨标志物Msx2、Cbfa1和Alpl以及I型胶原（Col1a1）、III型胶原（Col3a1）和纤维连接蛋白（Fbn） mRNA表达。这些影响与胆钙化醇处理小鼠主动脉Casr mRNA表达的增加是平行的，MgCl2进一步增强了这种表达。结论：MgCl2对VSMCs成骨/软骨转化和血管钙化的保护作用涉及调节CASR和CASR依赖性信号传导。
Objectives: The progression of vascular calcification, an active process promoted by osteo/chondrogenic transformation of vascular smooth muscle cells (VSMCs) is attenuated by activation of the calcium-sensing receptor (CASR). Recent in-vitro studies revealed that vascular calcification could be blunted by Mg2+, but the underlying mechanisms remained elusive. The present study explored whether the effects of MgCl2 on vascular calcification involve the CASR.Methods: Experiments were performed in primary human aortic smooth muscle cells (HAoSMCs) and in the mouse vascular calcification model of vitamin D-3 overload.Results: Phosphate-induced calcium deposition and mRNA expression of the osteogenic markers msh homeobox 2 (MSX2), CBFA1 (core-binding factor a 1), and ALPL (tissue-nonspecific alkaline phosphatase) in HAoSMCs were blunted by additional treatment with MgCl2. MgCl2 upregulated CASR mRNA expression in HAoSMCs in a dose-dependent manner. Furthermore, the inhibitory effects of MgCl2 on phosphate-induced calcium deposition and osteogenic markers mRNA expression were mimicked by the CASR agonist GdCl3 and reversed by additional treatment with the CASR antagonist NPS-2143 or by silencing of the CASR gene in HAoSMCs. MgCl2 also blunted the osteogenic transformation of VSMCs induced by hydroxyapatite particles. High-dosed cholecalciferol treatment induced vascular calcification and upregulated aortic osteogenic markers Msx2, Cbfa1 and Alpl and collagen type I (Col1a1), collagen type III (Col3a1) and fibronectin (Fbn) mRNA expression in mice, effects reduced by additional treatment with MgCl2. These effects were paralleled by increased aortic Casr mRNA expression in cholecalciferol-treated mice, which was further augmented by MgCl2.Conclusion: The protective effects of MgCl2 on osteo/chondrogenic transformation of VSMCs and vascular calcification involve regulation of CASR and CASR-dependent signaling.