Gut Microbial Metabolite Trimethylamine N-Oxide Aggravates Pulmonary Hypertension
Gut Microbial Metabolite Trimethylamine N-Oxide Aggravates Pulmonary Hypertension
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DOI：
10.1165/rcmb.2021-0414oc
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发表时间：
2022-04-01
影响因子：
6.4
通讯作者：
Wang, Tao
中科院分区：
文献类型：
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作者：
Huang, Yuhang;Lin, Fanjie;Wang, Tao
氧化三甲胺（Trimethylamine N-oxide，TMAO）是一种来源于肠道微生物植物群的代谢产物，可增强多种心血管疾病的血管炎症反应，肺动脉高压（pulmonary hypertension，PH）患者体内与TMAO代谢相关的细菌群落数量较多。然而，TMAO对PH的影响尚未阐明。在本研究中，与健康对照组或低风险PH患者相比，发现中度至高风险PH患者的循环TMAO升高。在野百合碱诱导的大鼠PH模型中，循环TMAO升高;并且在野百合碱诱导的大鼠PH和缺氧诱导的小鼠PH模型中，使用3，3-二甲基-1-丁醇（DMB）减少TMAO显著降低右心室收缩压和肺血管肌化。大鼠肺的RNA测序显示，DMB处理显著抑制了参与精氨酸-细胞因子受体相互作用以及细胞因子和趋化因子信号传导的途径。蛋白质-蛋白质相互作用分析的差异表达的转录物调节DMB显示了五个枢纽基因的促炎细胞因子和趋化因子，包括Kng 1，Cxcl 1，Cxcl 2，Cxcl 6，和IL 6的强连接。体外实验表明，TMAO可显著增加骨髓源性巨噬细胞Kng 1、Cxcl 1、Cxcl 2、Cxcl 6和IL 6的表达。TMAO处理的巨噬细胞条件培养液可促进肺动脉平滑肌细胞的增殖和迁移，但TMAO处理对肺动脉平滑肌细胞的增殖和迁移无明显影响。总之，我们的研究表明，TMAO在重度PH中增加，并且TMAO的减少通过抑制巨噬细胞产生趋化因子和细胞因子来减少肺血管肌化并减轻PH。
Trimethylamine N-oxide (TMAO), a metabolite derived from intestine microbial flora, enhances vascular inflammation in a variety of cardiovascular diseases, and the bacterial communities associated with TMAO metabolism are higher in pulmonary hypertension (PH) patients. The effects of TMAO on PH, however, have not been elucidated. In the present study, circulating TMAO was found to be elevated in intermediate to high-risk PH patients when compared with healthy control or low-risk PH patients. In monocrotaline-induced rat PH models, circulating TMAO was elevated; and reduction of TMAO using 3,3-dimethyl-1-butanol (DMB) significantly decreased right ventricle systolic pressure and pulmonary vascular muscularization in both monocrotaline-induced rat PH and hypoxia-induced mouse PH models. RNA sequencing of rat lungs revealed that DMB treatment significantly suppressed the pathways involved in cytokine-cytokine receptor interaction and in cytokine and chemokine signaling. Protein-protein interaction analysis of the differentially expressed transcripts regulated by DMB showed five hub genes with a strong connectivity of proinflammatory cytokines and chemokines, including Kng1, Cxcl1, Cxcl2, Cxcl6, and Il6. In vitro, TMAO significantly increased the expression of Kng1, Cxcl1, Cxcl2, Cxcl6, and Il6 in bone-marrow-derived macrophage. Also, TMAO-treated conditioned medium from macrophage increased the proliferation and migration of pulmonary artery smooth muscle cells, but TMAO treatment did not change the proliferation or migration of pulmonary artery smooth muscle cells. In conclusion, our study demonstrates that TMAO is increased in severe PH, and the reduction of TMAO decreases pulmonary vascular muscularization and alleviates PH by suppressing the macrophage production of chemokines and cytokines.