SKQ1 Improves Trimethylamine-N-Oxide-Induced Endothelial Dysfunction by Attenuating Oxidative Stress and Restoring Junctional Proteins

Abstract

In recent years, the role of microbiota and microbial metabolites in the progress of aging and age-related diseases has been attracting increased attention. In this context, trimethylamine N-oxide (TMAO) is a pro-atherogenic and pro-inflammatory metabolite derived from the gut microbial metabolism of trimethylamine and is found to be elevated in patients with age-related cardiovascular disorders. We identified that TMAO treatment in mice has enhanced mitochondrial ROS production, endoplasmic reticulum stress and caused significant endothelial dysfunction. The present study investigated whether mitochondria-targeted antioxidant SKQ1 protected against TMAO-induced endothelial dysfunction. Endothelial cells were treated with or without TMAO (30μM) in the cell culture media. TMAO treated cells showed significant increase in both total ROS as well as mito-ROS production compared to untreated control group (n=8/group; p<0.05). In addition, western blot analysis demonstrated that TMAO treatment significantly decreased tight junction proteins such as occludin, ZO-1 and VE-Cadherin which were restored upon SKQ1 treatment (150nM, 12h). TMAO (30μM) treatment for 24 h induced significant mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential, increased mitochondrial ROS levels, and enhanced endothelial cell permeability compared to the control group (n=8/group; p<0.05). Treatment with a SKQ1 (150nM, 12h) significantly inhibited TMAO-induced ROS production and protected against increased endothelial cell permeability and mitochondrial ROS production (n=8/group; p<0.05). In conclusion, mitochondria-targeted antioxidant SKQ1 protects against TMAO induced endothelial dysfunction by attenuating ROS production and disruption of tight junction proteins. This work is supported by NIH R01 HL148711 award to Saisudha Koka This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.