Increased circulating trimethylamine N-oxide contributes to endothelial dysfunction in a rat model of chronic kidney disease
Increased circulating trimethylamine N-oxide contributes to endothelial dysfunction in a rat model of chronic kidney disease
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DOI：
10.1016/j.bbrc.2017.12.069
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发表时间：
2018-01-08
影响因子：
3.1
通讯作者：
Chen, Yanli
中科院分区：
文献类型：
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作者：
Li, Tiejun;Gua, Chaojun;Chen, Yanli
慢性肾脏病（CKD）与心血管风险增加密切相关。在CKD患者中已经报道了血管内皮功能受损，这是心血管疾病发病机制的关键起始步骤，但CKD中导致内皮功能障碍的机制仍然难以理解。新出现的证据表明，由肠道微生物群产生的代谢物三甲基胺-N-氧化物（TMAO）参与了许多心血管疾病的发病机制。CKD患者的循环TMAO升高。在这里，我们测试的假设，即TMAO升高在CKD内皮功能障碍的发病机制中起着促进作用。将大鼠进行5/6肾切除以诱导CKD或假手术，并用1.0%3，3-二甲基-1-丁醇（DMB，一种三甲胺形成的抑制剂）或溶剂处理。肾切除术和DMB治疗后8周，与假载体大鼠相比，CKD载体大鼠的循环TMAO水平显著升高，但在CKD-DMB大鼠中降低。与假溶剂大鼠相比，CKD溶剂大鼠中乙酰胆碱诱导的内皮依赖性血管舒张受损，表现为最大舒张（Emax）降低和曲线下面积（AUC）降低。CKD-DMB大鼠的Emm和AUC均正常化。各组间硝普钠诱导的内皮非依赖性血管舒张无差异。分子生物学研究表明，与假手术组大鼠相比，CKD-载体大鼠的主动脉内皮一氧化氮合酶活性降低，而超氧化物生成和促炎细胞因子表达增加。值得注意的是，上述分子参数的异常在CKD-DMB大鼠中完全恢复。这些结果表明，CKD升高循环TMAO水平，这可能通过增加血管氧化应激和炎症减少eNOS衍生的NO产生，从而导致CKD相关的内皮功能障碍和心血管疾病。(C)2017爱思唯尔公司All rights reserved.
Chronic kidney disease (CKD) is strongly associated with increased cardiovascular risk. Impaired endothelial function, a key initiating step in the pathogenesis of cardiovascular disease, has been reported in patients with CKD, but the mechanisms responsible for endothelial dysfunction in CKD remain elusive. Emerging evidence reveals that trimethylamine-N-oxide (TMAO), a gut microbiota-generated metabolite, is involved in the pathogenesis of many cardiovascular diseases. Circulating TMAO is elevated in CKD. Here we tested the hypothesis that elevated TMAO plays a contributory role in the pathogenesis of endothelial dysfunction in CKD. Rats underwent 5/6 nephrectomy to induce CKD or sham operation, and were treated with 1.0% 3,3-Dimethyl-l-butanol (DMB, an inhibitor of trimethylamine formation) or vehicle. Eight weeks after nephrectomy and DMB treatment, circulating TMAO levels were markedly elevated in CKD-vehicle rats compared with sham-vehicle rats, but were reduced in CKD-DMB rats. Acetylcholine-induced endothelium-dependent vasodilation was impaired in CKD-vehicle rats compared with sham-vehicle rats as indicated by reduced maximal relaxation (Emax) and decreased area under the curve (AUC). Emm, and AUC were both normalized in CKD-DMB rats. No difference in sodium nitroprusside-induced endothelial-independent vasodilation was observed across groups. Molecular studies revealed that endothelial nitric-oxide synthase activity was decreased, while superoxide production and proinflammatory cytokine expression were increased in the aorta of CKD-vehicle rats compared with sham-vehicle rats. Of note, the abnormalities in above molecular parameters were completely restored in CKD-DMB rats. These results suggest that CKD elevates circulating TMAO levels, which may reduce eNOS-derived NO production by increasing vascular oxidative stress and inflammation, contributing to CKD-associated endothelial dysfunction and cardiovascular disease. (C) 2017 Elsevier Inc. All rights reserved.