(P01-044-20) Choline Treatment Activates NLRP3 Inflammasome Formation and Leads to Endothelial Dysfunction in Mice
Objectives: Choline and other trimethylamine-containing nutrients are metabolized by gut microbiota into Trimethylamine N-oxide (TMAO), which is involved in the pathogenesis of various cardiovascular diseases. The present study was designed to investigate the relation between dietary choline and endothelial dysfunction in mice.
Methods: Nlrp3 +/+ and Nlrp3 -/- mice were treated with 3% choline chloride in drinking water for 6 months. Plasma concentration of TMAO levels were measured after the treatment. Cardiac and endothelial dysfunction were monitored using echocardiography. Vascular permeability was measured by Evans blue dye perfusion. Confocal microscopy was used to detect the co-localization of Nlrp3 inflammasome components. Caspase-1 activity was measured by colorimetric assay and IL-1β production was measured using ELISA. Western blotting was used to measure tight-junction proteins. Real time PCR analysis was used to determine the TLR-4 and inflammatory markers (ICAM and VCAM) in the carotid arteries of the mice.
Results: Choline treatment significantly increased plasma TMAO levels in all the groups. Choline treated Nlrp3+/+ mice showed significant impairment in endothelial function and had increased vascular hyper-permeability, enhanced Nlrp3 activation and decreased expression of tight junction proteins like ZO2, VE-cadherin and occludin expression in carotid arteries compared to choline treated Nlrp3-/- mice. Caspase-1 activity and IL-1β production was significantly enhanced in choline treated Nlrp3+/+ mice but not in Nlrp3-/-mice. Real time PCR analysis showed that TLR-4 and inflammatory markers (ICAM & VCAM) were significantly increased in carotid arteries of choline treated Nlrp3+/+ mice compared to Nlrp3-/- mice.
Conclusions: Our results suggest that chronic choline treatment induced endothelial dysfunction via activation of Nlrp3 inflammasome and other inflammatory markers.
Funding Sources: NIH - NHLBI, AHA
Assistant Professor University of Houston Houston, Texas