Gut microbiota dependent trimethylamine N-oxide aggravates angiotensin II–induced hypertension

Jiang, Shan; Shui, Yongjie; Yu, Changmin; Tang, Chun; Wang, Xiaohua; Qiu, Xingyu; Hu, Weipeng; Fei, Lingyan; Li, Yun; Zhang, Suping; Zhao, Liang; Xu, Nan; Dong, Fang; Ren, Xiaoqiu; Liu, Ruisheng; Persson, Pontus B.; Patzak, Andreas; Lai, En Yin; Wei, Qichun; Zheng, Zhihua

doi:10.1016/j.redox.2021.102115

Cited by 116 publications

(90 citation statements)

References 68 publications

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“…A meta-analysis of a large population showed that individuals with high TMAO were more likely to develop hypertension, and there was a significant positive dose-dependent association between circulating TMAO concentrations and hypertension risk ( Ge et al, 2020 ). Jiang et al demonstrated that hypertensive patients had higher plasma TMAO than normotensive controls, and TMAO facilitated Ang II-induced vasoconstriction to aggravate Ang II-induced hypertension ( Jiang et al, 2021 ). TMAO also contributes to the age-related endothelial dysfunction via oxidative stress in mice and human ( Brunt et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…A meta-analysis of large population showed that there was a significant positive dose-dependent association between circulating TMAO and prevalence of hypertension ( Ge et al, 2020 ). Moreover, gut microbiota metabolite TMAO is showed to facilitate Ang II-induced vasoconstriction and hypertension ( Jiang et al, 2021 ). Hence, TMAO is emerged as a potential therapeutic target for hypertension and vascular dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Berberine Improves Vascular Dysfunction by Inhibiting Trimethylamine-N-oxide via Regulating the Gut Microbiota in Angiotensin II-Induced Hypertensive Mice

Wang

Zhou

et al. 2022

Front. Microbiol.

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Berberine (BBR) has been demonstrated to exert cardiovascular protective effects by regulating gut microbiota. However, few studies examine the effect of BBR on the gut microbiota in hypertension. This study aims to investigate the role of BBR in regulating microbial alterations and vascular function in hypertension. C57BL/6 J mice were infused with Ang II (0.8 mg/kg/day) via osmotic minipumps and treated with BBR (150 mg/kg/day) or choline (1%) for 4 weeks. Blood pressure was detected by tail-cuff measurement once a week. Abdominal aorta pulse wave velocity (PWV) and endothelium dependent vasodilatation were measured to evaluate vascular function. Vascular remodeling was assessed by histological staining of aortic tissue. The fecal microbiota was profiled using 16S ribosomal DNA (rDNA) sequencing. Plasma trimethylamine (TMA)/trimethylamine-N-oxide (TMAO) and hepatic FMO3 expression were measured. We found that BBR treatment significantly alleviated the elevated blood pressure, vascular dysfunction, and pathological remodeling in Ang II-induced hypertensive mice, while choline treatment aggravated hypertension-related vascular dysfunction. 16S rDNA gene sequencing results showed that BBR treatment altered gut microbiota composition (reduced the Firmicutes/Bacteroidetes (F/B) ratio and increased the abundances of Lactobacillus). Moreover, BBR inhibited FMO3 expression and plasma TMA/TMAO production in hypertensive mice. TMAO treatment increased the apoptosis and oxidative stress of human aortic endothelial cells (HAECs) and aggravated Ang II-induced HAECs dysfunction in vitro. These results indicate that the protective effect of BBR in hypertension might be attributed (at least partially) to the inhibition of TMAO production via regulating the gut microbiota.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Berberine Improves Vascular Dysfunction by Inhibiting Trimethylamine-N-oxide via Regulating the Gut Microbiota in Angiotensin II-Induced Hypertensive Mice

Wang

Zhou

et al. 2022

Front. Microbiol.

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“…Gut bacteria of taxa Erysipelotrichia produce TMA following choline metabolization, thus decreasing the bioavailability of this macronutrient and increasing the portal influx of TMA and its conversion to trimethylamine N-oxide (TMAO). This small metabolite [ 642 , 643 , 644 , 645 , 646 , 647 , 648 ] is associated with atherosclerosis and cardiovascular complications, including myocardial infarction and stroke [ 646 , 649 , 650 , 651 , 652 ]. In addition, increased TMAO levels correlate with the presence of type 2 diabetes mellitus, glycemic control in type 2 diabetes mellitus, its complications, and steatogenic effects [ 653 , 654 , 655 , 656 , 657 , 658 , 659 ].…”

Section: Intestinal Barrier Features In Nafldmentioning

confidence: 99%

Intestinal Barrier and Permeability in Health, Obesity and NAFLD

et al. 2021

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The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.

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“…Plasma trimethylamine N-oxide (TMAO), a metabolite of the dietary lipid phosphatidylcholine, has been proven to be associated with an increased risk of major cardiovascular diseases in both human and animal-model studies [ 4 , 5 ]. TMAO has been demonstrated to activate protein kinase-like ER kinase and enhance reactive oxygen species (ROS) generation in VSMC, which augmented angiotensin II -induced vasoconstriction [ 6 ]. However, a clear mechanistic link between TMAO and vascular inflammation is not yet established.…”

Section: Introductionmentioning

confidence: 99%

PRMT5 critically mediates TMAO-induced inflammatory response in vascular smooth muscle cells

et al. 2022

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A high plasma level of the choline-derived metabolite trimethylamine N-oxide (TMAO) is closely related to the development of cardiovascular disease. However, the underlying mechanism remains unclear. In the present study, we demonstrated that a positive correlation of protein arginine methyltransferase 5 (PRMT5) expression and TMAO-induced vascular inflammation, with upregulated vascular cell adhesion molecule-1 (VCAM-1) expression in primary rat and human vascular smooth muscle cells (VSMC) in vitro. Knockdown of PRMT5 suppressed VCAM-1 expression and the adhesion of primary bone marrow-derived macrophages to TMAO-stimulated VSMC. VSMC-specific PRMT5 knockout inhibited vascular inflammation with decreased expression of VCAM-1 in mice. We further identified that PRMT5 promoted VCAM-1 expression via symmetrical demethylation of Nuclear factor-κB p65 on arginine 30 (R30). Finally, we found that TMAO markedly induced the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) and production of reactive oxygen species, which contributed to PRMT5 expression and subsequent VCAM-1 expression. Collectively, our data provide novel evidence to establish a Nox4-PRMT5-VCAM-1 in mediating TMAO-induced VSMC inflammation. PRMT5 may be a potential target for the treatment of TMAO-induced vascular diseases.

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Gut microbiota dependent trimethylamine N-oxide aggravates angiotensin II–induced hypertension

Cited by 116 publications

References 68 publications

Berberine Improves Vascular Dysfunction by Inhibiting Trimethylamine-N-oxide via Regulating the Gut Microbiota in Angiotensin II-Induced Hypertensive Mice

Berberine Improves Vascular Dysfunction by Inhibiting Trimethylamine-N-oxide via Regulating the Gut Microbiota in Angiotensin II-Induced Hypertensive Mice

Intestinal Barrier and Permeability in Health, Obesity and NAFLD

PRMT5 critically mediates TMAO-induced inflammatory response in vascular smooth muscle cells

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