RNA-Seq analysis TMAO effect on vascular smooth muscle cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE226668 | GEO | 2026/06/30
REPOSITORIES: GEO
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Project description:We utilized human aortic vascular smooth muscle cells (HAVSMCs) treated with saline or trimethylamine N-oxide (TMAO) for 5 hours
2023-01-02 | GSE200143 | GEO
Project description:Background: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular event characterized by high mortality rates. Previous studies have shown that matrix metalloproteinases 19 (MMP19) was involved in TAAD formation, while the detailed role of MMP19 in TAAD pathogenesis and underlying mechanism remain unclear. Methods: To investigate the role of MMP19 in the progression of TAAD, we generated global Mmp19 knockout mice, as well as VSMCs (vascular smooth muscle cells)-specific Mmp19 knockdown mice, and established a BAPN-induced TAAD model. To elucidate the signaling pathways modulated by Aggrecan, we employed an adeno-associated virus serotype 9 (AAV9) vector encoding Acan short hairpin RNA (shRNA) for VSMC-specific knockdown of Acan. Ultimately, we injected an AAV vector encoding VSMC-specific Mmp19 into BAPN-induced TAAD mice to assess whether MMP19 can mitigate the development of TAAD. Results: Our findings revealed elevated mRNA and protein levels of MMP19 in the aortas of both TAAD mice and patients. The systemic ablation of Mmp19, as well as VSMC-specific Mmp19 knockdown, significantly exacerbated BAPN-induced progressive TAAD, and TAAD-related cardiovascular remodeling. Mmp19 deficiency resulted in the accumulation of Acan, but not Vcan, within the aorta, driving the phenotypic switch of VSMCs from contractile to synthetic state through activting Wnt/β-catenin signaling pathway. The selective inhibitor of Wnt/β-catenin signaling, MASB, was effective in reversing the dedifferentiation of VSMCs induced by aggrecan accumulation. Notably, the specific knockdown of Acan in VSMCs restored the contractile phenotype of VSMCs and inhibited Wnt/β-catenin signaling, thereby alleviating BAPN-induced TAAD in Mmp19-/- mice. Additionally, VSMC-specific complementation of MMP19 also alleviated the progressive TAAD phenotype in Mmp19-/- mice. Conclusions: The study underscores that MMP19 deficiency exacerbates TAAD by promoting Acan aggregation and destroying the homeostasis of VSMCs by activating Wnt/β-catenin signaling pathway. These results posit MMP19 as a promising novel therapeutic target for TAAD intervention.
2025-04-01 | GSE287828 | GEO
Project description:Lysyl oxidase is an extracellular enzyme essential for crosslinking elastin and collagen. Mice that do not express Lox have 60% and 40% reductions in elastin-specific and collagen-specific crosslinks, respectively. Mutations in LOX are associated with thoracic aortic aneurysm and dissection (TAAD). Lysyl oxidase knockout mice dye perinatally with ruptured diaphragm, tortuous arteries, and TAAD This is the first study to analyze the mechanical and genetic changes induced by the absence of lysyl oxidase in the thoracic aorta, and may provide new therapeutic targets relevant for the pathogenesis of thoracic aortic aneurysms and dissections
2016-10-28 | GSE89227 | GEO
Project description:Cardiovascular diseases (CVDs) are leading causes of death worldwide. Endothelial dysfunction is a critical initiating factor contributing to CVDs, which progression involves the gut microbiome-derived metabolite Trimethylamine N-oxide (TMAO). Here, we aim to clarify the time-dependent pathways by which TMAO mediates endothelial dysfunction.
2023-11-23 | GSE235204 | GEO
Project description:Liver cancer has a high mortality rate. Chronic inflammation is one of the leading causes of hepatocellular carcinoma. Recent studies suggested high levels of trimethylamine N-oxide (TMAO) may correlate with increased risk of inflammatory-induced liver cancer. However, the mechanisms by which TMAO promotes liver cancer remain elusive. Here, we established a model of inflammatory-induced liver cancer by treating Hepa1-6 cells with TNF-α. TMAO synergistically increased the proliferation, migration and invasion of Hepa1-6 cells in the presence of TNF-α. We conducted bulk RNA-Seq of the TMAO-treated cell model of inflammatory Hepatocellular carcinoma (HCC)
2022-01-18 | GSE193557 | GEO
Project description:Circulating trimethylamine N-oxide (TMAO) participates in the pathogenesis of cardio-metabolic diseases, with hepatic flavin-containing monooxygenase 3 (FMO3) originally regarded as the primary source of TMAO production. Here, we demonstrate that white adipose tissue (WAT) expressed FMO3 and its derived metabolic product TMAO causatively contribute to the systemic elevation of TMAO levels, WAT dysfunction, and metabolic diseases in ageing. We showed that FMO3 expression and TMAO levels are upregulated in WAT of naturally ageing animals and human subjects, as well as in a DNA damage-induced senescent adipocyte model, but not in the liver. This upregulation is due to p53 activation in mice and could be mitigated by calorie restriction in humans. Adipocyte-specific ablation of FMO3 attenuates TMAO accumulation in WAT and circulation, leading to enhanced glucose metabolism, energy homeostasis, and lipid regulation in aged and high-fat diet-induced obese mice. Transcriptomic and histological analysis link these metabolic improvements to reduced senescence, fibrosis, and inflammation in WAT as well as a decrease in adipose-resident macrophages. LiP-small molecule mapping (LiP-SMap) analysis identified numerous novel TMAO-interacting proteins implicated in inflammasome activation within white adipocytes and macrophages. Mechanistically, TMAO facilitates inflammasome activation by binding to the inflammasome adaptor protein apoptosis-associated speck-like protein containing A CARD (ASC), thereby inducing its expression, caspase-1 activation, and subsequent interleukin-1β (IL-1β) production. Our findings uncover a pivotal role for adipocyte FMO3 in modulating TMAO production and WAT dysfunction by promoting inflammasome activation in ageing via an autocrine and paracrine manner.
2025-08-23 | PXD066391 | Pride
Project description:Trimethylamine-N-oxide (TMAO) is a uremic toxin, which has been associated with chronic kidney disease (CKD). Renal tubular epithelial cells play a central role in the pathophysiology of CKD. Megalin is an albumin-binding surface receptor on tubular epithelial cells, which is indispensable for urine protein reabsorption. To date, no studies have investigated the effect of TMAO on megalin expression and the functional properties of human tubular epithelial cells. The aim of this study was first to identify the functional effect of TMAO on human renal proximal tubular cells and second, to unravel the effects of TMAO on megalin-cubilin receptor expression. We found through global gene expression analysis that TMAO was associated with kidney disease. The microarray analysis also showed that megalin expression was suppressed by TMAO, which was also validated at the gene and protein level. High glucose and TMAO was shown to downregulate megalin expression and albumin uptake similarly. We also found that TMAO suppressed megalin expression via PI3K and ERK signaling. Furthermore, we showed that candesartan, dapagliflozin and enalaprilat counter-acted the suppressive effect of TMAO on megalin expression. Our results may further help us un-ravel the role of TMAO in CKD development and to identify new therapeutic targets to counteract TMAOs effects.
2022-08-10 | GSE210692 | GEO
Project description:Circulating trimethylamine N-oxide (TMAO) participates in the pathogenesis of cardio-metabolic diseases, with hepatic flavin-containing monooxygenase 3 (FMO3) originally regarded as the primary source of TMAO production. Here, we demonstrate that white adipose tissue (WAT) expressed FMO3 and its derived metabolic product TMAO causatively contribute to the systemic elevation of TMAO levels, WAT dysfunction, and metabolic diseases in ageing. We showed that FMO3 expression and TMAO levels are upregulated in WAT of naturally ageing animals and human subjects, as well as in a DNA damage-induced senescent adipocyte model, but not in the liver. This upregulation is due to p53 activation in mice and could be mitigated by calorie restriction in humans. Adipocyte-specific ablation of FMO3 attenuates TMAO accumulation in WAT and circulation, leading to enhanced glucose metabolism, energy homeostasis, and lipid regulation in aged and high-fat diet-induced obese mice. Transcriptomic and histological analysis link these metabolic improvements to reduced senescence, fibrosis, and inflammation in WAT as well as a decrease in adipose-resident macrophages. LiP-small molecule mapping (LiP-SMap) analysis identified numerous novel TMAO-interacting proteins implicated in inflammasome activation within white adipocytes and macrophages. Mechanistically, TMAO facilitates inflammasome activation by binding to the inflammasome adaptor protein apoptosis-associated speck-like protein containing A CARD (ASC), thereby inducing its expression, caspase-1 activation, and subsequent interleukin-1β (IL-1β) production. Our findings uncover a pivotal role for adipocyte FMO3 in modulating TMAO production and WAT dysfunction by promoting inflammasome activation in ageing via an autocrine and paracrine manner.
2025-07-17 | GSE294785 | GEO
Project description:Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide(TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT), and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic ER stress and inflammation in part by decreasing hepatic oxysterol levels and subsequent LXR activation. FMO3 is thus identified as a central integrator of hepatic cholesterol and triacylglycerol metabolism, inflammation, and ER stress. These studies suggest that the gut microbiota-driven TMA/FMO3/TMAO pathway is a key regulator of lipid metabolism and inflammation.
2014-12-19 | GSE64326 | GEO
Project description:Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide(TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT), and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic ER stress and inflammation in part by decreasing hepatic oxysterol levels and subsequent LXR activation. FMO3 is thus identified as a central integrator of hepatic cholesterol and triacylglycerol metabolism, inflammation, and ER stress. These studies suggest that the gut microbiota-driven TMA/FMO3/TMAO pathway is a key regulator of lipid metabolism and inflammation. To identify potential regulators of macrophage reverse cholesterol transport (RCT), liver was isolated from two independent mouse models where the non-biliary RCT pathway known as transintestinal cholesterol excretion (TICE) was either chronically (NPC1L1-liver-transgenic mice) or acutely (ACAT2 antisense oligonucleotide treatment) stimulated. Total RNA was isolated and gene expression levels were profiled on the Affymetrix GeneAtlas MG-430 PM Array Strip (Affymetrix; Santa Clara, CA, USA)
2014-12-19 | E-GEOD-64326 | biostudies-arrayexpress