Department of Cardiovascular, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China.
Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt B):113209. doi: 10.1016/j.intimp.2024.113209. Epub 2024 Sep 27.
The endothelial-mesenchymal transition (EndMT) is involved in the development of atherosclerosis (AS) and is a key process in vascular endothelial injury. Oxidative stress, inflammation, and apoptosis are common causes of EndMT, and EndMT progression can further accelerate the development of AS. The metabolite trimethylamine N-oxide (TMAO) is produced by the gut microbiome and is implicated in the development of several diseases, including diabetes and chronic kidney disease. However, the impact of TMAO on transforming growth factor β1(TGF-β1)-induced EndMT remains unclear. We hypothesize that TMAO exacerbates plaque formation and cardiac function impairment by promoting EndMT. Herein, we showed that high serum TMAO levels caused plaque formation, cardiac function damage and haemodynamic changes in ApoE mice. In vitro, TMAO upregulated mesenchymal markers and downregulated endothelial markers in HAECs. Furthermore, TMAO increased the migratory capacity of EndMT cells. Mechanistically, we found that PERK downregulation could alleviate TMAO-induced oxidative stress, EndMT, plaque formation and cardiac function damage. Further study showed that activated transcription factor 3 (ATF3), the downstream molecule of protein kinase RNA-like endoplasmic reticulum kinase (PERK), could bind with TGF-β1/2 and affect EndMT. Overall, TMAO promotes EndMT, possibly through the PERK-eIF2α-ATF4-CHOP or the PERk-eIF2α-ATF3-TGF-β signalling pathways.
内皮-间充质转化（EndMT）参与动脉粥样硬化（AS）的发生发展，是血管内皮损伤的关键过程。氧化应激、炎症和细胞凋亡是 EndMT 的常见原因，EndMT 的进展可进一步加速 AS 的发展。代谢物三甲胺 N-氧化物（TMAO）由肠道微生物群产生，与多种疾病的发生有关，包括糖尿病和慢性肾脏病。然而，TMAO 对转化生长因子 β1（TGF-β1）诱导的 EndMT 的影响尚不清楚。我们假设 TMAO 通过促进 EndMT 加剧斑块形成和心脏功能损伤。在此，我们发现高血清 TMAO 水平可导致 ApoE 小鼠形成斑块、心脏功能损伤和血液动力学改变。在体外，TMAO 可在上皮细胞中上调间充质标志物和下调内皮标志物。此外，TMAO 增加了 EndMT 细胞的迁移能力。在机制上，我们发现 PERK 下调可减轻 TMAO 诱导的氧化应激、EndMT、斑块形成和心脏功能损伤。进一步的研究表明，蛋白激酶 RNA 样内质网激酶（PERK）下游分子激活转录因子 3（ATF3）可与 TGF-β1/2 结合并影响 EndMT。总的来说，TMAO 促进 EndMT 的发生，可能是通过 PERK-eIF2α-ATF4-CHOP 或 PERK-eIF2α-ATF3-TGF-β 信号通路。
