Trimethylamine N‐oxide promotes apoE^−/− mice atherosclerosis by inducing vascular endothelial cell pyroptosis via the SDHB/ROS pathway

Abstract

Trimethylamine N-oxide (TMAO) is produced from the phosphatidylcholine metabolism of gut flora and acts as a risk factor of cardiovascular disease.However, the underlying mechanisms for its proatherogenic action remain unclear.This study aimed to observe the effect of TMAO on endothelial cell pyroptosis and explore the underlying mechanisms. Our results showed that TMAO promoted the progression of atherosclerotic lesions in apolipoprotein E-deficient (apoE −/− ) mice fed a high-fat diet. Pyroptosis and succinate dehydrogenase complex subunit B (SDHB) upregulation were detected in the vascular endothelial cells of apoE −/− mice and in cultured human umbilical vein endothelial cells (HUVECs) treated with TMAO. Overexpression of SDHB in HUVECs enhanced pyroptosis and impaired mitochondria and high reactive oxygen species (ROS) level. Pyroptosis in the SDHB overexpression of endothelial cells was inhibited by the ROS scavenger NAC. In summary, TMAO promotes vascular endothelial cell pyroptosis via ROS induced through SDHB upregulation, thereby contributing to the progression of atherosclerotic lesions.

Implication of Gut Microbiota in Cardiovascular Diseases

“…As a type of proinflammatory cell death, pyroptosis is characterized by swollen cells, subcellular organelle damage, and the release of cytokines, including the NLRP3 inflammasome, NLRP6, an apoptosis-associated speck-like protein containing CARD (ASC), cysteinyl-aspartate-specific proteinase 1 (caspase-1), and gasdermin D. Data have shown that sodium butyrate is capable of breaking down the gingival epithelial barrier by inducing pyroptosis [ 52 ]. Similarly, TMAO promotes vascular endothelial cell pyroptosis via ROS production, thus resulting in the development of atherosclerosis [ 53 ]. However, Gu et al proved the antipyroptosis effects of sodium butyrate on renal glomerular endothelial cells, protecting them from damage caused by high glucose [ 54 ].…”

Influence of Microbial Metabolites on the Nonspecific Permeability of Mitochondrial Membranes under Conditions of Acidosis and Loading with Calcium and Iron Ions

“…With regard to the relationship between TMAO and mitochondrial dysfunctions, of interest are the data showing a coupled increase in the level of TMAO, citrate and 2-oxoglutarate in urinary metabolomic profile in model experiments in rats with active or relapsing vasculitis [ 48 ]. In addition, TMAO promoted endothelial cell pyroptosis, a programmed cell death characterized by plasma membrane rupture via mitochondrial ROS production induced by SDH upregulation [ 49 ]. According to our data, TMAO stimulated mitochondrial swelling only under acidification and did not affect either calcium-induced MPTP opening or iron-induced swelling.…”

Dexmedetomidine Attenuates LPS-Induced Monocyte-Endothelial Adherence via Inhibiting Cx43/PKC-α/NOX2/ROS Signaling Pathway in Monocytes

“…Multiple studies have shown that ROS can activate NF- κ B, JNK/SAPK, and p38 MAPK signaling pathways [ 36 ]. In vascular endothelial cells, ROS can result in the upregulation of adhesion of molecule expression significantly, increase monocyte-endothelial adherence, and ultimately atherosclerosis [ 37 ]. Rains et al report that ROS can result in the increase of LFA-1 on monocytes [ 36 ].…”