Trimethylamine N-Oxide Promotes Abdominal Aortic Aneurysm Formation by Aggravating Aortic Smooth Muscle Cell Senescence in Mice

Hu, Jiaxin; Xu, Jiamin; Shen, Song; Zhang, Wengfeng; Chen, Haiting; Sun, Xuan; Qi, Yu; Zhang, Ying; Zhang, Qi; Guo, Meng; Peng, Ningxin; Xu, Baojun

doi:10.1007/s12265-022-10211-6

Cited by 10 publications

(7 citation statements)

References 31 publications

(37 reference statements)

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“…In contrast to a previous study suggesting that TMAO-induced aneurysm formation was attributable to upregulated VSMC senescence, we found that senescent genes CDKN1A (p21), CDKN2C (p14/p16), and GLB (β-galactosidase) were decreased in our human VSMCs treated with TMAO (Figure S8A) and our in vivo model (Figure S8B). 36 Overall, these data confirm a relationship between TMAO and PERK-mediated UPR and, together with our in vivo data, suggest that TMAO mechanistically contributes to AAA through activation of PERK-mediated UPR and VSMC apoptosis.…”

Section: Resultssupporting

confidence: 85%

Gut Microbiota–Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms

Benson

Conrad

et al. 2023

Circulation

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Background: Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention. Methods: TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor–deficient ( Ldlr −/− ) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 ( Fmo3 −/− ). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA. Results: Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition, Fmo3 −/− mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells–augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK. Conclusions: These results define a role for gut microbiota–generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress–related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.

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Section: Resultssupporting

confidence: 85%

Gut Microbiota–Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms

Benson

Conrad

et al. 2023

Circulation

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“…Hu et al. revealed that TMAO induces smooth muscle cell calcification and vascular senescence and promotes AAA formation in mice models [ 19 ]. Furthermore, when apolipoprotein E-deficient mice were fed a high-choline diet, the blood TMAO level increased and arteriosclerosis worsened [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of <i>Bifidobacterium adolescentis</i> in patients with abdominal aortic aneurysm: a cross-sectional study

Ito

Ohki

Toya

et al. 2023

Bioscience of Microbiota, Food and Health

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The relationships between various diseases and the human gut microbiota (GM) have been revealed. However, the relationships between the human abdominal aortic aneurysm (AAA) and GM remains unknown. The aim of this cross-sectional study was to clarify the association between the human AAA and GM. Stool samples from 30 consecutive patients with AAA before aneurysm repair and those of 30 controls without vascular diseases were analyzed by 16S rRNA gene (V3-4) sequencing using an Illumina MiSeq system and QIIME 2. There was no significant difference in age (75 vs. 75 years) or gender (80% vs. 87% males) between the groups. No significant difference in GM composition was observed in principal coordinate analysis between the two groups, whereas the AAA group showed a significantly lower abundance of B. adolescentis (p < 0.01) at the species level than the controls. This study demonstrated that the abundance of B. adolescentis decreased in patients with AAA. This is the first study to show the characteristics of the GM in patients with AAA. Studies are needed to reveal if causal relationships exists between the human AAA and GM.

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“…The role of TMAO in AAA has been recently suggested. TMAO added to drinking water promoted AAA development in Ang II and CaCl 2 mouse models ( 241 ). This was accompanied by heightened elastin degradation and upregulation of ROS, MMP-2 and 9 and senescence markers in the aorta ( 241 ).…”

Section: Mechanisms That Regulate Immune Cells In Aaamentioning

confidence: 99%

Immune and inflammatory mechanisms of abdominal aortic aneurysm

Márquez-Sánchez

Koltsova

2022

Front. Immunol.

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Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. Immune-mediated infiltration and a destruction of the aortic wall during AAA development plays significant role in the pathogenesis of this disease. While various immune cells had been found in AAA, the mechanisms of their activation and function are still far from being understood. A better understanding of mechanisms regulating the development of aberrant immune cell activation in AAA is essential for the development of novel preventive and therapeutic approaches. In this review we summarize current knowledge about the role of immune cells in AAA and discuss how pathogenic immune cell activation is regulated in this disease.

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Trimethylamine N-Oxide Promotes Abdominal Aortic Aneurysm Formation by Aggravating Aortic Smooth Muscle Cell Senescence in Mice

Cited by 10 publications

References 31 publications

Gut Microbiota–Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms

Gut Microbiota–Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms

Impact of <i>Bifidobacterium adolescentis</i> in patients with abdominal aortic aneurysm: a cross-sectional study

Immune and inflammatory mechanisms of abdominal aortic aneurysm

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