Trimethylamine-N-Oxide Promotes Vascular Calcification Through Activation of NLRP3 (Nucleotide-Binding Domain, Leucine-Rich-Containing Family, Pyrin Domain-Containing-3) Inflammasome and NF-κB (Nuclear Factor κB) Signals
Trimethylamine-N-Oxide Promotes Vascular Calcification Through Activation of NLRP3 (Nucleotide-Binding Domain, Leucine-Rich-Containing Family, Pyrin Domain-Containing-3) Inflammasome and NF-κB (Nuclear Factor κB) Signals
复制标题
三甲胺-N-氧化物通过激活 NLRP3（核苷酸结合域、富含亮氨酸的家族、含 Pyrin 域的 3）炎症小体和 NF-kappa B（核因子 kappa B）信号促进血管钙化
DOI：
10.1161/atvbaha.119.313414
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发表时间：
2020-03-01
影响因子：
8.7
通讯作者：
Chen, Minsheng
中科院分区：
文献类型：
--
作者：
Zhang, Xiuli;Li, Yining;Chen, Minsheng
目的：血管钙化在慢性肾脏病患者中非常普遍。在接受血液透析的患者中发现血浆三甲胺 N-氧化物 (TMAO) 浓度升高，TMAO 是一种肠道微生物群依赖性产物。然而，TMAO 和血管钙化之间的明确机制联系尚未建立。在本研究中，我们利用体外、离体和体内模型研究TMAO是否参与血管钙化的进展。方法和结果：茜素红染色显示TMAO以剂量依赖性方式促进钙/磷酸盐诱导的大鼠和人血管平滑肌细胞的钙化，钙含量测定证实了这一点。同样，TMAO上调骨相关分子的表达，包括Runx2（Runt相关转录因子2）和BMP2（骨形态发生蛋白2），表明TMAO促进血管平滑肌细胞的成骨分化。此外，离体研究还显示TMAO对血管钙化具有积极的调节作用。此外，微计算机断层扫描分析、茜素红染色和钙含量测定表明，TMAO 加速了慢性肾病大鼠的血管钙化。相比之下，通过抗生素降低TMAO水平可以减轻慢性肾病大鼠的血管钙化。有趣的是，TMAO 在血管钙化过程中激活了 NLRP3（核苷酸结合域、富含亮氨酸家族、pyrin 域-3）炎性体和 NF-kappa B（核因子 kappa B）信号。抑制NLRP3炎症小体和NF-κB信号可减弱TMAO诱导的血管平滑肌细胞钙化。结论：本研究首次证明TMAO通过激活NLRP3炎症小体和NF-κB信号促进血管钙化，提示肠道微生物代谢与血管钙化之间存在潜在联系。降低TMAO水平可能成为慢性肾病血管钙化的潜在治疗策略。
Objectives:Vascular calcification is highly prevalent in patients with chronic kidney disease. Increased plasma trimethylamine N-oxide (TMAO), a gut microbiota-dependent product, concentrations are found in patients undergoing hemodialysis. However, a clear mechanistic link between TMAO and vascular calcification is not yet established. In this study, we investigate whether TMAO participates in the progression of vascular calcification using in vitro, ex vivo, and in vivo models.Approach and Results:Alizarin red staining revealed that TMAO promoted calcium/phosphate-induced calcification of rat and human vascular smooth muscle cells in a dose-dependent manner, and this was confirmed by calcium content assay. Similarly, TMAO upregulated the expression of bone-related molecules including Runx2 (Runt-related transcription factor 2) and BMP2 (bone morphogenetic protein-2), suggesting that TMAO promoted osteogenic differentiation of vascular smooth muscle cells. In addition, ex vivo study also showed the positive regulatory effect of TMAO on vascular calcification. Furthermore, we found that TMAO accelerated vascular calcification in rats with chronic kidney disease, as indicated by Mico-computed tomography analysis, alizarin red staining and calcium content assay. By contrast, reducing TMAO levels by antibiotics attenuated vascular calcification in chronic kidney disease rats. Interestingly, TMAO activated NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome and NF-kappa B (nuclear factor kappa B) signals during vascular calcification. Inhibition of NLRP3 inflammasome and NF-kappa B signals attenuated TMAO-induced vascular smooth muscle cell calcification.Conclusions:This study for the first time demonstrates that TMAO promotes vascular calcification through activation of NLRP3 inflammasome and NF-kappa B signals, suggesting the potential link between gut microbial metabolism and vascular calcification. Reducing the levels of TMAO could become a potential treatment strategy for vascular calcification in chronic kidney disease.