Wnt1 inhibits vascular smooth muscle cell calcification by promoting ANKH expression
Wnt1 inhibits vascular smooth muscle cell calcification by promoting ANKH expression
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Wnt1通过促进ANKH表达抑制血管平滑肌细胞钙化
DOI：
10.1016/j.yjmcc.2019.07.008
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发表时间：
2019-10-01
影响因子：
5
通讯作者：
Zhao, Gexin
中科院分区：
文献类型：
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作者：
Chen, Beidong;Zhao, Yang;Zhao, Gexin
目的：Wnt信号在血管钙化（VC）中起关键作用。Wnt因子对心血管功能有不同的生理和病理影响。Wntl是Wnt/ β -连环蛋白信号的配体，可促进血管生成，减少心肌梗死。Wnt1在慢性肾脏疾病（CKD）中对VC的作用尚不完全清楚。方法和结果：我们利用人血管平滑肌细胞（VSMCs）和慢性肾功能衰竭（CRF）大鼠模型，观察了通过激活Wnt1及其转录靶ANKH无机焦磷酸盐运输调节因子（ANKH）基因来降低VC的天然保护机制。ANKH是一种必需的钙化抑制剂，可从VSMCs外排无机焦磷酸盐（PPi），在VC中发挥抑制作用。CRF模型大鼠血管ANKH和血浆PPi显著下调。ANKH的下调或抑制逆转了Wnt1对VSMCs中VC的影响。临床分析显示低血浆Wnt1和PPi水平与CKD患者相关。应用Wnt/ β -连环蛋白信号激动剂可以缓解VC的进展。结论：ANKH对VSMCs中Wntl的调控对VC的阻断至关重要。我们的发现可能有助于开发针对Wnt信号和/或ANKH抑制VC的药物。
Aims: Wnt signaling plays a critical role in vascular calcification (VC). Wnt factors induce different physiological and pathological effects on cardiovascular functions. Wntl, a ligand of Wnt/beta-catenin signaling, promotes proangiogenesis and reduces myocardial infarction. The role of Wnt1 on VC in chronic kidney disease (CKD) is not fully understood.Methods and results: We used human vascular smooth muscle cells (VSMCs) and a rat model of chronic renal failure (CRF), and observed a native protective mechanism by which VC is reduced via the activation of Wnt1 and its transcriptional target ANKH inorganic pyrophosphate transport regulator (ANKH) gene. ANKH is an essential calcification inhibitor that effluxes inorganic pyrophosphate (PPi) from VSMCs to play an inhibitory role in VC. Vascular ANKH and plasma PPi were significantly downregulated in the rat model of CRF. The knockdown or inhibition of ANKH reversed the effect of Wnt1 on VC in VSMCs. Clinical analysis revealed low plasma levels of Wnt1 and PPi were associated with CKD in patients. Applying a Wnt/beta-catenin signaling agonist can alleviate the progression of VC.Conclusion: This work reveals the ANKH regulation of Wntl in VSMCs is essential for blocking VC. Our findings may contribute to the development of medications that target Wnt signaling and/or ANKH to inhibit VC.