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The gut microbe-derived metabolite trimethylamine-N-oxide induces aortic valve fibrosis via PERK/ATF-4 and IRE-1α/XBP-1s signaling in vitro and in vivo.
- Source :
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Atherosclerosis (00219150) . Apr2024, Vol. 391, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
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Abstract
- The gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) has been implicated in the development of cardiovascular fibrosis. Endoplasmic reticulum (ER) stress occurs after the dysfunction of ER and its structure. The three signals PERK/ATF-4, IRE-1α/XBP-1s and ATF6 are activated upon ER stress. Recent reports have suggested that the activation of PERK/ATF-4 and IRE-1α/XBP-1s signaling contributes to cardiovascular fibrosis. However, whether TMAO mediates aortic valve fibrosis by activating PERK/ATF-4 and IRE-1α/XBP-1s signaling remains unclear. Human aortic valve interstitial cells (AVICs) were isolated from aortic valve leaflets. PERK IRE-1α, ATF-4, XBP-1s and CHOP expression, and production of collagen Ⅰ and TGF-β1 were analyzed following treatment with TMAO. The role of PERK/ATF-4 and IRE-1α/XBP-1s signaling pathways in TMAO-induced fibrotic formation was determined using inhibitors and small interfering RNA. Diseased valves produced greater levels of ATF-4, XBP-1, collagen Ⅰ and TGF-β1. Interestingly, diseased cells exhibited augmented PERK/ATF-4 and IRE-1α/XBP-1s activation after TMAO stimulation. Inhibition and silencing of PERK/ATF-4 and IRE-1α/XBP-1s each resulted in enhanced suppression of TMAO-induced fibrogenic activity in diseased cells. Mice treated with dietary choline supplementation had substantially increased TMAO levels and aortic valve fibrosis, which were reduced by 3,3-dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) treatment. Moreover, a high-choline and high-fat diet remodeled the gut microbiota in mice. TMAO promoted aortic valve fibrosis through activation of PERK/ATF-4 and IRE-1α/XBP-1s signaling pathways in vitro and in vivo. Modulation of diet, gut microbiota, TMAO, PERK/ATF-4 and IRE1-α/XBP-1s may be a promising approach to prevent aortic valve fibrosis. [Display omitted] • ATF-4 and XBP-1 are activated in human aortic valves. • PERK/ATF-4 and IRE-1α/XBP-1s signaling promotes TMAO-induced fibrotic formation in VICs. • Supplemental choline and fat diet remodels the gut microbiota and elevates circulating TMAO levels. • Elevated circulating TMAO increases aortic valve fibrosis in vivo. [ABSTRACT FROM AUTHOR]
- Subjects :
- *AORTIC valve
*CHOLINE
*SMALL interfering RNA
*FIBROSIS
*DIETARY fats
*GUT microbiome
Subjects
Details
- Language :
- English
- ISSN :
- 00219150
- Volume :
- 391
- Database :
- Academic Search Index
- Journal :
- Atherosclerosis (00219150)
- Publication Type :
- Academic Journal
- Accession number :
- 176502202
- Full Text :
- https://doi.org/10.1016/j.atherosclerosis.2023.117431