Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan.
Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Antioxid Redox Signal. 2023 Jan;38(1-3):215-233. doi: 10.1089/ars.2021.0115.
Trimethylamine-N-oxide (TMAO) is a metabolite generated from dietary choline, betaine, and l-carnitine, after their oxidization in the liver. TMAO has been identified as a novel independent risk factor for atherosclerosis through the induction of vascular inflammation. However, the effect of TMAO on neointimal formation in response to vascular injury remains unclear. This study was conducted using a murine model of acutely disturbed flow-induced atherosclerosis induced by partial carotid artery ligation. 3,3-Dimethyl-1-butanol (DMB) was used to reduce TMAO concentrations. Wild-type mice were divided into four groups [regular diet, high-TMAO diet, high-choline diet, and high-choline diet+DMB] to investigate the effects of TMAO elevation and its inhibition by DMB. Mice fed high-TMAO and high-choline diets had significantly enhanced neointimal hyperplasia and advanced plaques, elevated arterial elastin fragmentation, increased macrophage infiltration and inflammatory cytokine secretion, and enhanced activation of nuclear factor (NF)-κB, the NLRP3 inflammasome, and endoplasmic reticulum (ER) stress relative to the control group. Mice fed high-choline diets with DMB treatment exhibited attenuated flow-induced atherosclerosis, inflammasome expression, ER stress, and reactive oxygen species expression. Human aortic smooth muscle cells (HASMCs) were used to investigate the mechanism of TMAO-induced injury. The HASMCs were treated with TMAO with or without an ER stress inhibitor to determine whether inhibition of ER stress modulates the TMAO-induced inflammatory response. This study demonstrates that TMAO regulates vascular remodeling via ER stress. Our findings demonstrate that TMAO elevation promotes disturbed flow-induced atherosclerosis and that DMB administration mitigates vascular remodeling, suggesting a rationale for a TMAO-targeted strategy for the treatment of atherosclerosis. 38, 215-233.
氧化三甲胺（TMAO）是在肝脏中氧化胆碱、甜菜碱和左旋肉碱等饮食来源的代谢产物。TMAO 已被确定为通过诱导血管炎症的新型独立动脉粥样硬化风险因素。然而，TMAO 对血管损伤后新生内膜形成的影响尚不清楚。 本研究采用部分颈动脉结扎诱导的急性血流紊乱性动脉粥样硬化小鼠模型进行。使用 3,3-二甲基-1-丁醇（DMB）降低 TMAO 浓度。将野生型小鼠分为四组[常规饮食、高 TMAO 饮食、高胆碱饮食和高胆碱饮食+DMB]，以研究 TMAO 升高及其对 DMB 的抑制作用。与对照组相比，高 TMAO 和高胆碱饮食组的小鼠新生内膜增生和高级斑块明显增强，动脉弹性蛋白碎片化增加，巨噬细胞浸润和炎症细胞因子分泌增加，核因子（NF）-κB、NLRP3 炎性小体和内质网（ER）应激激活增强。用 DMB 处理高胆碱饮食的小鼠表现出减弱的血流诱导的动脉粥样硬化、炎性小体表达、ER 应激和活性氧表达。用人主动脉平滑肌细胞（HASMCs）研究 TMAO 诱导损伤的机制。用 TMAO 处理 HASMCs 或用 ER 应激抑制剂处理 HASMCs，以确定抑制 ER 应激是否调节 TMAO 诱导的炎症反应。 本研究表明，TMAO 通过 ER 应激调节血管重塑。我们的研究结果表明，TMAO 升高促进了血流紊乱诱导的动脉粥样硬化，DMB 给药减轻了血管重塑，提示针对 TMAO 的策略治疗动脉粥样硬化具有合理性。38,215-233.
