Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis
Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis
复制标题
肠道微生物衍生的代谢物三甲胺 N-氧化物可诱导心脏肥大和纤维化。
DOI：
10.1038/s41374-018-0091-y
复制
发表时间：
2019-03-01
影响因子：
5
通讯作者：
Chen, Minsheng
中科院分区：
文献类型：
--
作者：
Li, Zehua;Wu, Zhiye;Chen, Minsheng
氧化三甲胺（TMAO）是一种肠道微生物来源的胆碱和其他含三甲胺营养素的代谢物，与心血管疾病风险增加有关。目前还不清楚TMAO是否在心脏肥大的发展中起作用。采用SD大鼠行主动脉缩窄术（TAC）诱导心肌肥厚。我们观察到，在SD大鼠TAC 6周后，TMAO水平显著升高，提示TMAO在调节心肌肥厚中的潜在作用。在培养的心肌细胞中，TMAO处理刺激心脏肥大，如心肌细胞的细胞面积增加和肥大标志物包括心房利钠肽（ANP）和β-肌球蛋白重链（β-MHC）的表达所示。此外，TMAO治疗诱导SD大鼠心脏肥大和心脏纤维化。通过抗生素（Abs）减少TMAO合成可减弱TAC诱导的心脏肥大和纤维化。SIS 3对Smad 3的药理学抑制可显著降低TMAO处理组的ANP和β-MHC表达，并降低心肌细胞大小。这些数据首次证明，肠道微生物衍生的代谢产物TMAO诱导涉及Smad 3信号的心脏肥大和纤维化，表明抑制肠道微生物或产生TMAO可能成为预防和治疗心脏肥大的潜在靶点。
Trimethylamine N-oxide (TMAO), a gut microbe-derived metabolite of dietary choline and other trimethylamine-containing nutrients, has been linked to increased cardiovascular disease risk. It is unknown whether TMAO plays a role in the development of cardiac hypertrophy. Transverse aortic constriction (TAC) was performed to induce cardiac hypertrophy in Sprague-Dawley (SD) rats. We observed that TMAO levels were significantly elevated in SD rats after 6 weeks of TAC, suggesting the potential role of TMAO in regulating cardiac hypertrophy. In cultured cardiomyocytes, TMAO treatment stimulated cardiac hypertrophy, as indicated by increased cell area of cardiomyocytes and expression of hypertrophic markers including atrial natriuretic peptide (ANP) and beta-myosin heavy chain (beta-MHC). Additionally, TMAO treatment induced cardiac hypertrophy and cardiac fibrosis in SD rats. Reducing TMAO synthesis by antibiotics (Abs) attenuated TAC-induced cardiac hypertrophy and fibrosis. Furthermore, pharmacological inhibition of Smad3 by SIS3 significantly reduced the expression of ANP and beta-MHC, and cardiomyocyte cell size in TMAO-treated group. These data for the first time demonstrate that gut microbe-derived metabolite TMAO induces cardiac hypertrophy and fibrosis involving Smad3 signaling, suggesting that inhibition of gut microbes or generation of TMAO may become a potential target for the prevention and treatment of cardiac hypertrophy.