A novel role of FKN/CX3CR1 in promoting osteogenic transformation of VSMCs and atherosclerotic calcification
A novel role of FKN/CX3CR1 in promoting osteogenic transformation of VSMCs and atherosclerotic calcification
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FKN/CX3CR1在促进VSMC成骨转化和动脉粥样硬化钙化中的新作用
DOI：
10.1016/j.ceca.2020.102265
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发表时间：
2020-11-01
期刊：
影响因子：
4
通讯作者：
Zhang, Lili
中科院分区：
文献类型：
--
作者：
Yang, Tong;Guo, Lu;Zhang, Lili
Fractalkine（FKN）及其特异性受体CX 3CR 1在动脉粥样硬化的发病机制中起关键作用，包括血管细胞的募集和炎症的发展。然而，其对调节动脉粥样硬化钙化的发展的贡献尚未得到很好的证明。血管平滑肌细胞（VSMCs）的成骨转化在动脉粥样硬化病变钙化的发展中至关重要。在这项研究中，我们首次评估了FKN/CX 3CR 1对VSMCs钙化进展的影响，并定义了在FKN/CX 3CR 1诱导的VSMCs成骨转化中起作用的分子信号传导。我们发现，高脂饮食诱导的动脉粥样硬化钙化在载脂蛋白E（ApoE）和CX 3CR 1（-/-）缺陷（ApoE（-/-）/CX 3CR 1（-/-））小鼠体内显着抑制与他们的对照同窝仔。氧化低密度脂蛋白（ox-LDL）可上调FKN和CX 3CR 1的表达。FKN/CX 3CR 1以剂量依赖性方式促进成骨标志物（包括骨桥蛋白（OPN）、骨形态发生蛋白（BMP）-2和碱性磷酸酶（ALP））的表达，并降低VSMCs标志物（包括平滑肌（SM）α-肌动蛋白和SM 22-α）的表达。FKN/CX 3CR 1在VSMCs钙化中的重要作用通过慢病毒介导的CX 3CR 1的敲低或过表达阻断或加速VSMCs的成骨转化而得到进一步证实。这种反应分别与成骨因子、侏儒相关转录因子2（RUNX 2）、破骨细胞分化中的转录因子、核因子-κ B受体激活因子（RANK）、RANK配体（RANKL）和骨保护素（OPG）的相互上调和下调相关。通过Jak/Stat抑制剂AG 490抑制FKN/CX 3CR 1激活的Jak 2/Stat 3信号传导，同时阻断了VSMC的成骨转化和RUNX 2诱导。总之，我们的数据揭示了FKN/CX 3CR 1通过Jak 2/Stat 3信号通路激活RUNX 2和抑制OPG促进VSMC成骨转化和动脉粥样硬化钙化的新作用。我们的研究结果表明，靶向FKN/CX 3CR 1可能为预防和治疗动脉粥样硬化钙化提供新的策略。
Fractalkine (FKN) and its specific receptor CX3CR1 play a critical role in the pathogenesis of atherosclerosis including recruitment of vascular cells and the development of inflammation. However, its contribution to regulating the development of atherosclerotic calcification has not been well documented. Osteogenic transformation of vascular smooth muscle cells (VSMCs) is critical in the development of calcification in atherosclerotic lesions. In this study, for the first time, we evaluated the effect of FKN/CX3CR1 on the progression of VSMCs calcification and defined molecular signaling that is operative in the FKN/CX3CR1-induced osteogenic transformation of VSMCs. We found that high-fat diet induced atherosclerotic calcification in vivo was markedly inhibited in the Apolipoprotein E (ApoE) and CX3CR1 deficient (ApoE(-/-)/CX3CR1(-/-)) mice compared with their control littermates. FKN and CX3CR1 were both expressed in VSMCs and up-regulated by oxidized low-density lipoprotein (ox-LDL). FKN/CX3CR1 promoted the expression of osteogenic markers, including osteopontin (OPN), bone morphogenetic protein (BMP)-2 and alkaline phosphatase (ALP) and decreased VSMCs markers, including smooth muscle (SM) alpha-actin and SM22-alpha in a dose-dependent manner. The essential role of FKN/CX3CR1 in VSMCs calcification was further confirmed by lentivirus-mediated knockdown or over-expression of CX3CR1 blocked or accelerated osteogenic transformation of VSMCs. This response was associated with reciprocal up- and down-regulation of osteogenic factor, runt-related transcription factor 2 (RUNX2), transcription factors in osteoclast differentiation, receptor activator of nuclear factor-kappa B (RANK), RANK ligand (RNAKL) and osteoprotegerin (OPG), respectively. Inhibition of FKN/CX3CR1-activated Jak2/Stat3 signaling by the Jak/Stat inhibitor AG490 blocked osteogenic transformation of VSMCs and RUNX2 induction concurrently. Taken together, our data uncovered novel roles of FKN/CX3CR1 in promoting VSMC osteogenic transformation and atherosclerotic calcification by activating RUNX2 through Jak2/Stat3 signaling pathway and suppressing OPG. Our findings suggest that targeting FKN/CX3CR1 may provide new strategies for the prevention and treatment of atherosclerotic calcification.