Trimethylamine N-Oxide Exacerbates Cardiac Fibrosis via Activating the NLRP3 Inflammasome
Trimethylamine N-Oxide Exacerbates Cardiac Fibrosis via Activating the NLRP3 Inflammasome
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三甲胺 N-氧化物通过激活 NLRP3 炎症小体加剧心脏纤维化
DOI：
10.3389/fphys.2019.00866
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发表时间：
2019-07-09
影响因子：
4
通讯作者：
Wang, Lihong
中科院分区：
文献类型：
--
作者：
Li, Xueling;Geng, Jin;Wang, Lihong
背景/目的：据报道，肠道微生物群与心血管疾病的死亡率较高和预后较差相关。三甲胺N-氧化物（TMAO）是特定膳食营养素的肠道微生物群依赖性代谢产物，与心脏纤维化有关。近年来的研究表明，核巧酸结合寡聚化结构域（NOD）样受体蛋白3（NLRP 3）炎性体的激活促进了屯、脏纤维化。然而，TMAO是否通过激活NLRP 3炎性体介导心脏纤维化仍不清楚。方法和结果：为了确定TMAO介导的心脏纤维化的作用，我们建立了多柔比星（DOX）诱导的小鼠心脏纤维化模型，并在饮用水中加入或不加入TMAO。TMAO加重了DOX诱导的心功能障碍、心脏重量和心脏纤维化，表现为增强的胶原积累、更高的促纤维化水平和升高的炎性因子以及NLRP 3炎性体活化。采用原代培养的小鼠心肌成纤维细胞，结果表明TMAO通过TGF-β/Smad 3信号途径促进心肌成纤维细胞的增殖、迁移和胶原分泌，并呈剂量依赖性。此外，TMAO处理诱导培养的心脏成纤维细胞中的NLRP 3炎性小体活化，包括氧化应激。重要的是，NLRP 3的沉默在体外表现出对心脏纤维化的保护作用，包括细胞增殖、迁移和胶原沉积。结论：我们的数据表明，TMAO加重了DOX诱导的小鼠心脏纤维化，至少部分是通过激活NLRP 3炎性小体，为预防心脏纤维化的进展提供了一个新的潜在靶点。
Background/Aims: Gut microbiota has been reported to correlate with a higher mortality and worse prognosis of cardiovascular diseases. Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of specific dietary nutrients, which is linked to cardiac fibrosis. Recent reports have suggested that the activation of Nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome contributed to cardiac fibrosis. However, whether TMAO mediates cardiac fibrosis via activating NLRP3 inflammasome remains unclear. Methods and Results: To determine the role of TMAO–mediated cardiac fibrosis, we established mouse models of doxorubicin (DOX)-induced cardiac fibrosis with or without TMAO in drinking water. TMAO exacerbated DOX-induced cardiac dysfunction, heart weight and cardiac fibrosis manifested by enhanced collagen accumulation, higher profibrotic levels and elevated inflammatory factors as well as NLRP3 inflammasome activation. Using primary cultured mouse cardiac fibroblast, our results indicated that TMAO promoted proliferation, migration and collagen secretion in a dose-dependent manner by TGF-β/Smad3 signaling. Furthermore, TMAO treatment induced NLRP3 inflammasome activation including oxidative stress in cultured cardiac fibroblast. Importantly, the silencing of NLRP3 presented a protection effect against cardiac fibrosis including cellular proliferation, migration and collagen deposition in vitro. Conclusion: Our data suggested that TMAO aggravated DOX-induced mouse cardiac fibrosis, at least in part, through activation of the NLRP3 inflammasome, providing a new potential target for preventing the progression of cardiac fibrosis.