Elevated Circulating Trimethylamine N-Oxide Levels Contribute to Endothelial Dysfunction in Aged Rats through Vascular Inflammation and Oxidative Stress.
Elevated Circulating Trimethylamine N-Oxide Levels Contribute to Endothelial Dysfunction in Aged Rats through Vascular Inflammation and Oxidative Stress.
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DOI：
10.3389/fphys.2017.00350
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发表时间：
2017
影响因子：
4
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Li T;Chen Y;Gua C;Li X
血管内皮功能障碍是衰老过程的特征，是老年心血管疾病的重要危险因素。尽管血管炎症和氧化应激是衰老过程中内皮功能障碍的主要原因，但衰老过程中的潜在机制尚未完全了解。越来越多的证据表明，肠道微生物群依赖性代谢产物三甲胺-N-氧化物（TMAO）与许多心血管疾病的发病机制有关。我们检验了衰老增加循环TMAO水平的假设，TMAO水平诱导血管炎症和氧化应激，导致与年龄相关的内皮功能障碍。老年（22月龄）和年轻（4月龄）Fischer-344大鼠在饮用水中不含（对照）或含1.0% 3，3-二甲基-1-丁醇（DMB，一种三甲胺形成抑制剂）8周。与青年对照组相比，老年对照组血浆TMAO水平明显升高，经DMB治疗后，血浆TMAO水平降低。与年轻对照组相比，老年对照组的主动脉对乙酰胆碱的内皮依赖性舒张功能受损，表现为最大舒张（Emax）降低和曲线下面积（AUC）减少。在用DMB处理的老年大鼠中，Emax和AUC均正常化。各组间对硝普钠反应的内皮非依赖性舒张无差异。分子生物学研究显示，老年对照组主动脉中促炎细胞因子和超氧化物生成的表达增加，内皮型一氧化氮合酶（eNOS）的表达降低，经DMB治疗后均恢复。这些结果表明，老化增加循环TMAO水平，这可能会损害eNOS衍生的NO生物利用度增加血管炎症和氧化应激，导致老化相关的内皮功能障碍。
Vascular endothelial dysfunction, a characteristic of the aging process, is an important risk factor for cardiovascular disease in aging. Although, vascular inflammation and oxidative stress are major contributors to endothelial dysfunction in aging, the underlying mechanisms during the aging process are not fully understood. Accumulating evidence reveals that gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) is implicated in the pathogenesis of many cardiovascular diseases. We tested the hypothesis that aging increases circulating TMAO levels, which induce vascular inflammation and oxidative stress, resulting in age-associated endothelial dysfunction. Old (22-mo-old) and young (4-mo-old) Fischer-344 rats were treated without (control) or with 1.0% 3,3-Dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) in drinking water for 8 weeks. Compared with young control group, old control group had markedly higher plasma TMAO levels, which were reduced by DMB treatment. Endothelium-dependent relaxation of aorta in response to acetylcholine was impaired in old control group compared with young control group as indicated by decreased maximal relaxation (Emax) and reduced area under the curve (AUC). Emax and AUC were both normalized in old rats treated with DMB. No difference in endothelial-independent relaxation in response to sodium nitroprusside was observed among groups. Molecular studies revealed that old control group exhibits increased expression of proinflammatory cytokines and superoxide production, and decreased expression of endothelial nitric-oxide synthase (eNOS) in the aorta, all of which were restored by DMB treatment. These results suggest that aging increases circulating TMAO levels, which may impair eNOS-derived NO bioavailability by increasing vascular inflammation and oxidative stress, contributing to aging-associated endothelial dysfunction.