Trimethylamine-N-oxide (TMAO) promotes balloon injury-induced neointimal hyperplasia via upregulating Beclin1 and impairing autophagic flux

Hong, Qingqing; Que, Dongdong; Zhong, Chong‐Bin; Huang, Guanlin; Zhai, Weicheng; Chen, Deshu; Yan, Jing; Yang, Pingzhen

doi:10.1016/j.biopha.2022.113639

Cited by 3 publications

(4 citation statements)

References 68 publications

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“…TMAO concentrations in hemodialysis patients are 40-fold higher than control subjects ( 126 ), with ranges between 54.8 and 133.0 μM ( 127 ) and reach up to 1103.1 μM ( 26 ). TMAO concentration of 600 μM significantly increased expression of ICAM-1, IL1β, activated NLRP3 inflammasomes, induced EC inflammation, increased intracellular ROS ( 27 , 55 ), and promoted neointima hyperplasia ( 128 ). A previous study showed no association between serum TMAO levels and cardiovascular outcomes in ESRD patients ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways

Saaoud¹,

Liu²,

Xu³

et al. 2023

JCI Insight

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We determined whether gut microbiota-produced trimethylamine (TMA) is oxidized into trimethylamine N-oxide (TMAO) in non-liver tissues, whether TMAO promotes inflammation via trained immunity (TI) and made the following findings: Endoplasmic reticulum (ER) stress genes were co-upregulated with mitoCarta genes in chronic kidney diseases (CKD); TMAO upregulated 190 genes in human aortic endothelial cells (HAECs); TMAO synthesis enzyme flavin-containing monooxygenase 3 (FMO3) was expressed in human and mouse aortas,;4) TMAO trans-differentiated HAECs into innate immune cells; TMAO phosphorylated 12 kinases in cytosol via its receptor PERK and CREB, and integrated with PERK pathways; and PERK inhibitors suppressed TMAO-induced ICAM-1; TMAO upregulated 3 mitochondrial genes and downregulated inflammation inhibitor DARS2, induced mitoROS; and mitoTEMPO inhibited TMAO-induced ICAM-1; and -glucan priming followed by TMAO re-stimulation upregulated TNF- by inducing metabolic reprogramming; and glycolysis inhibitor suppressed TMAO-induced ICAM-1. Our results have provided novel insights over TMAO roles in inducing EC activation and innate immune trans-differentiation, inducing metabolic reprogramming and TI for enhanced vascular inflammation and new therapeutic targets for treating cardiovascular diseases (CVD), CKD-promoted CVD, inflammations, transplantation, aging, and cancers.

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Section: Discussionmentioning

confidence: 99%

Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways

Saaoud¹,

Liu²,

Xu³

et al. 2023

JCI Insight

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“…3 Metabolites in the blood microenvironment may have potential communication with endothelial function and then affect the development of CVD. 4,5 Therefore, understanding of the effects and molecular mechanisms of metabolites on endothelial function may provide more new perspectives for AS treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Endothelium lines on the vascular inner layer acting as the first barrier of blood vessels and maintain vascular homeostasis, also provide the main place where metabolites and factors communicate 3 . Metabolites in the blood microenvironment may have potential communication with endothelial function and then affect the development of CVD 4,5 . Therefore, understanding of the effects and molecular mechanisms of metabolites on endothelial function may provide more new perspectives for AS treatment.…”

Section: Introductionmentioning

confidence: 99%

N‐acetylneuraminic acid modulates SQSTM1/p62 sialyation‐mediated ubiquitination degradation contributing to vascular endothelium dysfunction in experimental atherosclerosis mice

Chen,

Qiu,

Chen

et al. 2023

IUBMB Life

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Sialic acid (SIA) has been reported to be a risk factor for atherosclerosis (AS) due to its high plasma levels in such patients. However, the effect of increasing SIA in circulation on endothelial function during AS progression remains unclear. In the present study, ApoE−/− mice and endothelial cells line (HUVEC cells) were applied to investigate the effect of SIA on AS progression and its potential molecular mechanism. In vivo, mice were injected intraperitoneally with Neu5Ac (main form of SIA) to keep high‐level SIA in circulation. ORO, H&E, and Masson staining were applied to detect the plaque progression. In vitro, HUVECs were treated with Neu5Ac at different times, CCK‐8, RT‐PCR, western blot, and immunoprecipitation methods were used to analyze its effects on endothelial function and the potential involved mechanism. Results from the present study showed that high plasma levels of Neu5Ac in ApoE−/− mice could aggravate the plaque areas as well as increase necrotic core areas and collagen fiber contents. Remarkably, Neu5Ac levels in circulation displayed a positive correlation with AS plaque areas. Furthermore, results from HUVECs showed that Neu5Ac inhibited cells viability in a time/dose‐dependent manner, by then induced the activation of inflammation makers such as ICAM‐1 and IL‐1β. Mechanism study showed that the activation of excessive autophagy medicated by SQSTM1/p62 displayed an important role in endothelium inflammatory injury. Neu5Ac could modify SQSTM1/p62 as a sialylation protein, and then increase its level with ubiquitin binding, further inducing ubiquitination degradation and being involved in the excessive autophagy pathway. Inhibition of sialylation by P‐3Fax‐Neu5Ac, a sialyltransferase inhibitor, reduced the binding of SQSTM1/p62 to ubiquitin. Together, these findings indicated that Neu5Ac increased SQSTM1/p62‐ubiquitin binding through sialylation modification, thereby inducing excessive autophagy and subsequent endothelial injury. Inhibition of SQSTM1/p62 sialylation might be a potential strategy for preventing such disease with high levels of Neu5Ac in circulation.

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“…However, to date, the mechanism of action of TMAO in PE remains unclear. Studies have found that abnormal oxidative stress in vivo can cause vascular endothelial cell damage 28 and placental trophoblast dysfunction, 3 representing one of the key factors leading to PE. In the present study, we observed that TMAO inhibited the migration and angiogenesis of HUVECs and the migration and invasion of HTR-8/SVneo cells in vitro, and the inhibitory effects of TMAO were reversed by NAC.…”

Section: Discussionmentioning

confidence: 99%

Gut microbiota-derived trimethylamine N-Oxide: a novel target for the treatment of preeclampsia

Wang,

Gao,

Ren

et al. 2024

Gut Microbes

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Pre-eclampsia (PE) is the most common complication of pregnancy and seriously threatens the health and safety of the mother and child. Studies have shown that an imbalance in gut microbiota can affect the progression of PE. Trimethylamine N-oxide (TMAO) is an intestinal microbiota-derived metabolite that is thought to be involved in the occurrence of PE; however, its causal relationship and mechanism remain unclear. In this clinical cohort study, including 28 patients with eclampsia and 39 matched healthy controls, fecal samples were collected for 16S rRNA gene sequencing, and serum was collected for targeted metabolomics research. The results showed that the level of TMAO and the abundance of its source bacteria had significantly increased in patients with PE, and were positively correlated with the clinical progression of PE. Fecal microbiota transplantation (FMT) was applied to an antibiotic-depleted-treated mouse model and targeted inhibition of TMAO. The results of the FMT experiment revealed that mice that received fecal microbiota transplantation from patients with PE developed typical PE symptoms and increased oxidative stress and inflammatory damage, both of which were reversed by 3,3-Dimethyl-1-butanol (DMB), a TMAO inhibitor, which also improved pregnancy outcomes in the model mice. Similar results were obtained in the classical NG-Nitroarginine methyl ester (L-NAME) induced PE mouse model. Mechanistically, TMAO promotes the progression of PE by regulating inflammatory and oxidative stress-related signaling pathways, affecting the migration and angiogenesis of vascular endothelial cells, as well as the migration and invasion of trophoblast cells. Our results reveal the role and mechanism of gut microbiota and TMAO in the progression of PE, provides new ideas for exploring the pathogenesis and therapeutic targets of PE, and determines the potential application value of TMAO as a target for PE intervention.

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Trimethylamine-N-oxide (TMAO) promotes balloon injury-induced neointimal hyperplasia via upregulating Beclin1 and impairing autophagic flux

Cited by 3 publications

References 68 publications

Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways

Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways

N‐acetylneuraminic acid modulates SQSTM1/p62 sialyation‐mediated ubiquitination degradation contributing to vascular endothelium dysfunction in experimental atherosclerosis mice

Gut microbiota-derived trimethylamine N-Oxide: a novel target for the treatment of preeclampsia

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