Gut flora-dependent metabolite Trimethylamine-N-oxide accelerates endothelial cell senescence and vascular aging through oxidative stress
Gut flora-dependent metabolite Trimethylamine-N-oxide accelerates endothelial cell senescence and vascular aging through oxidative stress
复制标题
肠道菌群依赖性代谢物三甲胺-N-氧化物通过氧化应激加速内皮细胞衰老和血管老化
DOI：
10.1016/j.freeradbiomed.2018.01.007
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发表时间：
2018-02-20
影响因子：
7.4
通讯作者：
Hong, Huashan
中科院分区：
文献类型：
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作者：
Ke, Yilang;Li, Dang;Hong, Huashan
氧化三甲胺（TMAO）是一种依赖肠道微生物群的代谢产物，已被证明与心血管疾病相关。然而，关于TMAO与血管衰老之间的关系却知之甚少。在此，我们观察了衰老过程中TMAO的变化，以及TMAO对血管衰老和内皮细胞（EC）衰老的影响。我们分析了年轻人（18 - 44岁）、老年人（≥65岁），以及1月龄、3月龄、6月龄和10月龄的快速老化小鼠8号品系（SAMP8）及其年龄匹配的抗快速老化小鼠1号品系（SAMR1）模型中与年龄相关的血浆TMAO水平。我们发现，在人类和小鼠中，循环TMAO水平均随年龄增长而升高。接下来，我们观察到，对SAMR1小鼠进行16周的TMAO处理可诱导血管衰老，而在SAMP8小鼠中则加速这一过程，这通过衰老相关β - 半乳糖苷酶（SA - β - gal）、p53和p21等衰老标志物的上调、血管功能障碍和重塑得以体现。在体外实验中，我们证明长期的TMAO处理可诱导人脐静脉内皮细胞（HUVECs）衰老，其特征为细胞增殖减少、衰老标志物表达增加、细胞停滞在G0/G1期以及细胞迁移受损。此外，TMAO在体内和体外均抑制沉默调节蛋白1（SIRT1）的表达并增加氧化应激，进而激活p53/p21/Rb通路，导致p53、p53乙酰化、p21增加，以及细胞周期蛋白依赖性激酶2（CDK2）、细胞周期蛋白E1（cyclinE1）和Rb磷酸化减少。总之，这些数据表明，衰老过程中循环TMAO水平升高可能会加剧内皮细胞衰老和血管衰老，这可能与SIRT1表达受抑制、氧化应激增加，进而激活p53/p21/Rb通路有关。
Trimethylamine-N-oxide (TMAO), gut microbiota-dependent metabolites, has been shown to be associated with cardiovascular diseases. However, little is known about the relationship between TMAO and vascular aging. Here, we observed a change in TMAO during the aging process and the effects of TMAO on vascular aging and endothelial cell (EC) senescence. We analyzed age-related plasma levels of TMAO in young adults (18-44 years old), older adults (>= 65 years old), and 1-month-old, 3-month-old, 6-month-old and 10-month-old senescence-accelerated mouse prone 8 (SAMP8) and age-matched senescence-accelerated mouse resistance 1 (SAMR1) models. We found that circulating TMAO increased with age both in humans and mice. Next, we observed that a TMAO treatment for 16 weeks induced vascular aging in SAMR1 mice and accelerated the process in SAMP8 mice, as measured by an upregulation of senescence markers including senescence-associated beta-galactosidase (SA-beta-gal), p53, and p21, vascular dysfunction and remodeling. In vitro, we demonstrated that prolonged TMAO treatment induced senescence in human umbilical vein endothelial cells (HUVECs), characterized by reduced cell proliferation, increased expressions of senescence markers, stagnate G0/G1, and impaired cell migration. Furthermore, TMAO suppressed sirtuin 1 (SIRT1) expression and increased oxidative stress both in vivo and in vitro and then activated the p53/p21/Rb pathway resulting in increased p53, acetylation of p53, p21, and decreased CDK2, cyclinE1, and phosphorylation of Rb. In summary, these data suggest that elevated circulating TMAO during the aging process may deteriorate EC senescence and vascular aging, which is probably associated with repression of SIRT1 expression and increased oxidative stress, and, thus, the activation of the p53/p21/Rb pathway.