氧化三甲胺与糖尿病患者血管重塑

doi:10.12092/j.issn.1009-2501.2026.06.006

摘要/Abstract

摘要：

血管重塑是糖尿病相关心脑血管疾病发生和发展的关键病理生理基础。近年来，氧化三甲胺（trimethylamine-N-oxide，TMAO）作为多种疾病新近的危险因素受到广泛关注。本文系统回顾了TMAO对血管内膜、中膜和外膜各层的调控作用，特别是其通过促进血管平滑肌细胞的表型转化、成纤维细胞的分化以及结构蛋白的异常改变，引发内膜增生、血管钙化和纤维化等血管重塑病理过程。同时，着重探讨了TMAO与糖尿病状态下血管重塑的复杂交互机制，包括晚期糖基化终产物及炎症和氧化应激的增强作用。基于当前研究进展，降低TMAO水平或阻断其相关信号通路可能成为干预血管重塑的新策略，为糖尿病血管并发症的防治提供新思路。

关键词: 氧化三甲胺, 血管重塑, 糖尿病, 心血管疾病, 肠道微生态

Abstract:

Vascular remodeling represents a key pathophysiological basis for the onset and progression of diabetes-related cardiovascular and cerebrovascular diseases. In recent years, trimethylamine-N-oxide (TMAO) has attracted considerable attention as a novel risk factor implicated in various diseases. This review systematically summarizes the regulatory effects of TMAO on the intima, media, and adventitia of blood vessels. In particular, we highlight how TMAO contributes to pathological vascular remodeling—such as intimal hyperplasia, calcification, and fibrosis—by promoting vascular smooth muscle cell phenotypic switching, fibroblast differentiation, and abnormal alterations in structural proteins. Moreover, we focus on the complex interplay between TMAO and vascular remodeling under diabetic conditions, emphasizing the enhancement of advanced glycation end products, inflammation, and oxidative stress. Based on recent findings, lowering TMAO levels or blocking its signaling pathways may offer promising strategies for intervening in vascular remodeling, providing novel insights into the prevention and treatment of diabetic vascular complications.

Key words: trimethylamine-N-oxide, vascular remodeling, diabetes, cardiovascular disease, gut microbiota

中图分类号:

R587.2

吴俊, 宋雨薇, 梁宏彪, 冯娟. 氧化三甲胺与糖尿病患者血管重塑[J]. 中国临床药理学与治疗学, 2026, 31(6): 774-781.

Jun WU, Yuwei SONG, Hongbiao LIANG, Juan FENG. Trimethylamine-N-oxide and vascular remodeling in patients with diabetes[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(6): 774-781.

图/表 1

参考文献 48

1	Ricciotti E, Haines PG, Chai W, et al. Prostanoids in cardiac and vascular remodeling[J]. Arterioscler Thromb Vasc Biol, 2024, 44 (3): 558- 583. doi: 10.1161/ATVBAHA.123.320045
2	Ye C, Zheng F, Wu N, et al. Extracellular vesicles in vascular remodeling[J]. Acta Pharmacol Sin, 2022, 43 (9): 2191- 2201. doi: 10.1038/s41401-021-00846-7
3	Zeng X, Yang Y. Molecular mechanisms underlying vascular remodeling in hypertension[J]. Rev Cardiovasc Med, 2024, 25 (2): 72. doi: 10.31083/j.rcm2502072
4	Huang X, Guo J, Ning A, et al. BAG3 promotes proliferation and migration of arterial smooth muscle cells by regulating STAT3 phosphorylation in diabetic vascular remodeling[J]. Cardiovasc Diabetol, 2024, 23 (1): 140. doi: 10.1186/s12933-024-02216-z
5	Caradonna E, Abate F, Schiano E, et al. Trimethylamine-N-Oxide (TMAO) as a rising-star metabolite: implications for human health[J]. Metabolites, 2025, 15 (4): 220. doi: 10.3390/metabo15040220
6	Tsikas D. Analysis, biology and significance of dimethylamine, trimethylamine and trimethylamine N-oxide in humans and in the marine ecosystem [J]. J Chromatogr B, 2025: 124602.
7	Kumari K, Singh KS, Singh K, et al. TMAO to the rescue of pathogenic protein variants [J]. Biochim Biophys Acta Gen Subj, 2022: 130214.
8	Latif F, Mubbashir A, Khan MS, et al. Trimethylamine N-oxide in cardiovascular disease: Pathophysiology and the potential role of statins [J]. Life Sci, 2024: 123304.
9	Jiang JY, Liu WM, Zhang QP, et al. Trimethylamine N-oxide aggravates vascular permeability and endothelial cell dysfunction under diabetic condition: in vitro and in vivo study[J]. Int J Ophthalmol, 2024, 17 (1): 25. doi: 10.18240/ijo.2024.01.04
10	Witkowski M, Witkowski M, Friebel J, et al. Vascular endothelial tissue factor contributes to trimethylamine N-oxide-enhanced arterial thrombosis[J]. Cardiovasc Res, 2022, 118 (10): 2367- 2384. doi: 10.1093/cvr/cvab263
11	Luciani M, Müller D, Vanetta C, et al. Trimethylamine-N-oxide is associated with cardiovascular mortality and vascular brain lesions in patients with atrial fibrillation[J]. Heart, 2023, 109 (5): 396- 404. doi: 10.1136/heartjnl-2022-321300
12	Zhu W, Wang Z, Tang WHW, et al. Gut microbe-generated trimethylamine N-oxide from dietary choline is prothrombotic in subjects[J]. Circulation, 2017, 135 (17): 1671- 1673. doi: 10.1161/CIRCULATIONAHA.116.025338
13	Rubenstein DA, Yin W. Platelet‐activation mechanisms and vascular remodeling[J]. Compr Physiol, 2018, 8 (3): 1117- 1156. doi: 10.1002/j.2040-4603.2018.tb00037.x
14	Gaikwad AV, Eapen MS, McAlinden KD, et al. Endothelial to mesenchymal transition (EndMT) and vascular remodeling in pulmonary hypertension and idiopathic pulmonary fibrosis[J]. Expert Rev Respir Med, 2020, 14 (10): 1027- 1043. doi: 10.1080/17476348.2020.1795832
15	彭园园, 陈碧莲. 氧化三甲胺影响冠心病和抗血小板药物疗效的研究进展[J]. 中国临床药理学与治疗学, 2024, 29 (5): 590.
16	Xu ZQ, Li XZ, Zhu R, et al. Asprosin contributes to vascular remodeling in hypertensive rats via superoxide signaling[J]. J Hypertens, 2024, 42 (8): 1427- 1439. doi: 10.1097/HJH.0000000000003751
17	Sun X, Jiao X, Ma Y, et al. Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome[J]. Biochem Biophys Res Commun, 2016, 481 (1/2): 63- 70. doi: 10.1016/j.bbrc.2016.11.017
18	Ma GH, Pan B, Chen Y, et al. Trimethylamine N-oxide in atherogenesis: impairing endothelial self-repair capacity and enhancing monocyte adhesion [J]. Biosci Rep, 2017, 37(2): BSR20160244.
19	Liu X, Shao Y, Tu J, et al. TMAO-activated hepatocyte-derived exosomes impair angiogenesis via repressing CXCR4 [J]. Front Cell Dev Biol, 2021, 9.
20	Kipshidze N, Dangas G, Tsapenko M, et al. Role of the endothelium in modulating neointimal formation: vasculoprotective approaches to attenuate restenosis after percutaneous coronary interventions[J]. J Am Coll Cardiol, 2004, 44 (4): 733- 739. doi: 10.1016/s0735-1097(04)01083-6
21	Hong Q, Que D, Zhong C, et al. Trimethylamine-N-oxide (tmao) promotes balloon injury-induced neointimal hyperplasia via upregulating Beclin1 and impairing autophagic flux[J]. Biomed Pharmacother, 2022, 155, 113639. doi: 10.1016/j.biopha.2022.113639
22	Chen CY, Leu HB, Wang SC, et al. Inhibition of trimethylamine N-oxide attenuates neointimal formation through reduction of inflammasome and oxidative stress in a mouse model of carotid artery ligation[J]. Antioxid Redox Signal, 2023, 38 (1-3): 215- 233. doi: 10.1089/ars.2021.0115
23	Deatrick KB, Eliason JL, Lynch EM, et al. Vein wall remodeling after deep vein thrombosis involves matrix metalloproteinases and late fibrosis in a mouse model[J]. J Vasc Surg, 2005, 42 (1): 140- 148. doi: 10.1016/j.jvs.2005.04.014
24	Sakao S, Tatsumi K. Crosstalk between endothelial cell and thrombus in chronic thromboembolic pulmonary hypertension: perspective[J]. Histol Histopathol, 2013, 28, 185- 193.
25	Zhu W, Gregory JC, Org E, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk[J]. Cell, 2016, 165 (1): 111- 124. doi: 10.1016/j.cell.2016.02.011
26	Li X, Li Y, Zhang L, et al. Trimethylamine N-oxide promotes vascular smooth muscle cell proliferation and migration via the AKT/mTOR signaling pathway in atherosclerosis[J]. J Cell Biochem, 2019, 120 (11): 19104- 19114.
27	Cheng X, Qiu X, Liu Y, et al. Trimethylamine N-oxide promotes tissue factor expression and activity in vascular endothelial cells: A new link between trimethylamine N-oxide and atherosclerotic thrombosis[J]. Thromb Res, 2019, 177, 110- 116. doi: 10.1016/j.thromres.2019.02.028
28	Jaminon A, Reesink K, Kroon A, et al. The role of vascular smooth muscle cells in arterial remodeling: focus on calcification-related processes[J]. Int J Mol Sci, 2019, 20 (22): 5694. doi: 10.3390/ijms20225694
29	Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease[J]. Physiol Rev, 2004, 84 (3): 767- 801. doi: 10.1152/physrev.00041.2003
30	Regnault V, Lacolley P, Laurent S. Arterial stiffness: from basic primers to integrative physiology[J]. Annu Rev Physiol, 2024, 86 (1): 99- 121. doi: 10.1146/annurev-physiol-042022-031925
31	Pan H, Xue C, Auerbach BJ, et al. Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human[J]. Circulation, 2020, 142 (21): 2060- 2075. doi: 10.1161/CIRCULATIONAHA.120.048378
32	Shi G, Zeng L, Shi J, et al. Trimethylamine N-oxide promotes atherosclerosis by regulating low-density lipoprotein-induced autophagy in vascular smooth muscle cells through PI3K/AKT/mTOR pathway[J]. Int Heart J, 2023, 64 (3): 462- 469. doi: 10.1536/ihj.22-603
33	Ortega MA, De Leon-Oliva D, Gimeno-Longas MJ, et al. Vascular calcification: molecular networking, pathological implications and translational opportunities[J]. Biomolecules, 2024, 14 (3): 275. doi: 10.3390/biom14030275
34	Yao H, Sun Z, Zang G, et al. Epidemiological research advances in vascular calcification in diabetes[J]. J Diabetes Res, 2021, 2021, 4461311.
35	Li J, Tan Y, Zhou P, et al. Association of trimethylamine N-oxide levels and calcification in culprit lesion segments in patients with st-segment-elevation myocardial infarction evaluated by optical coherence tomography[J]. Front Cardiovasc Med, 2021, 8, 628471. doi: 10.3389/fcvm.2021.628471
36	Zhang X, Li Y, Yang P, et al. Trimethylamine-N-oxide promotes vascular calcification through activation of NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome and NF-κB signals[J]. Arterioscler Thromb Vasc Biol, 2020, 40 (3): 751- 765. doi: 10.1161/ATVBAHA.119.313414
37	Majesky MW, Weiser-Evans MCM. The adventitia in arterial development, remodeling, and hypertension[J]. Biochem Pharmacol, 2022: 115259.
38	Coen M, Gabbiani G, Bochaton-Piallat ML. Myofibroblast-mediated adventitial remodeling: an underestimated player in arterial pathology[J]. Arterioscler Thromb Vasc Biol, 2011, 31 (11): 2391- 2396. doi: 10.1161/ATVBAHA.111.231548
39	Wan R, Weissman JP, Grundman K, et al. Diabetic wound healing: the impact of diabetes on myofibroblast activity and its potential therapeutic treatments[J]. Wound Repair Regen, 2021, 29 (4): 573- 581. doi: 10.1111/wrr.12954
40	Zou F, Li Y, Zhang S, et al. DP1 (prostaglandin D2 receptor 1) activation protects against vascular remodeling and vascular smooth muscle cell transition to myofibroblasts in angiotensin II–induced hypertension in mice[J]. Hypertension, 2022, 79 (6): 1203- 1215. doi: 10.1161/HYPERTENSIONAHA.121.17584
41	Cascino T, Csanyi G, Al Ghouleh I, et al. Adventitia-derived hydrogen peroxide impairs relaxation of the rat carotid artery via smooth muscle cell p38 mitogen-activated protein kinase[J]. Antioxid Redox Signal, 2011, 15 (6): 1507- 1515. doi: 10.1089/ars.2010.3631
42	Younesi FS, Miller AE, Barker TH, et al. Fibroblast and myofibroblast activation in normal tissue repair and fibrosis[J]. Nat Rev Mol Cell Biol, 2024, 25 (8): 617- 638. doi: 10.1038/s41580-024-00716-0
43	Kim SJ, Bale S, Verma P, et al. Gut microbe-derived metabolite trimethylamine N-oxide activates PERK to drive fibrogenic mesenchymal differentiation[J]. iScience, 2022, 25 (7): 104669. doi: 10.1016/j.isci.2022.104669
44	Brunt VE, Casso AG, Gioscia-Ryan RA, et al. Gut microbiome-derived metabolite trimethylamine N-oxide induces aortic stiffening and increases systolic blood pressure with aging in mice and humans[J]. Hypertension, 2021, 78 (2): 499- 511. doi: 10.1161/HYPERTENSIONAHA.120.16895
45	Zhu Y, Li Q, Jiang H. Gut microbiota in atherosclerosis: focus on trimethylamine N‐oxide[J]. APMIS, 2020, 128 (5): 353- 366. doi: 10.1111/apm.13038
46	Zhu GX, Zuo JL, Xu L, et al. Ginsenosides in vascular remodeling: Cellular and molecular mechanisms of their therapeutic action[J]. Pharmacol Res, 2021, 169, 105647. doi: 10.1016/j.phrs.2021.105647
47	Jin Q, Zhang C, Chen R, et al. Quinic acid regulated TMA/TMAO-related lipid metabolism and vascular endothelial function through gut microbiota to inhibit atherosclerotic[J]. J Transl Med, 2024, 22 (1): 352. doi: 10.1186/s12967-024-05120-y
48	Wang Z, Shao Y, Wu F, et al. Berberine ameliorates vascular dysfunction by downregulating TMAO-endoplasmic reticulum stress pathway via gut microbiota in hypertension[J]. Microbiol Res, 2024, 287, 127824. doi: 10.1016/j.micres.2024.127824

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