Gut Microbial Metabolite TMAO Induces Endothelial Dysfunction by Activating the HMGB1/TLR4 Signalling Pathway
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The intestinal microbe derived metabolite trimethylamine Noxide (TMAO) is implicated in the pathogenesis of cardiovascular diseases. However, the molecular mechanisms of how TMAO induces atherosclerosis and CVD progression are still unclear. In this regard, highmobility group box protein 1 (HMGB1), an inflammatory mediator, has been reported to destroy cellcell junctions, resulting in vascular endothelial hyper permeability leading to endothelial dysfunction. The present study tested whether TMAO associated endothelial dysfunction results via HMGB1 activation in in vitro and in vivo models. Biochemical and RTPCR analysis showed that TMAO increased the HMGB1 expression in dose dependent manner in endothelial cells compared to control cells. However, prior treatment with glycyrrhizin, an HMGB1 binder abolished the TMAOinduced HMGB1 production in endothelial cells. Furthermore, western blot and immunofluorescent analysis showed significant decrease in the expression of cellcell junction proteins ZO1, ZO2, Occludin and Vcadherin in TMAO treated endothelial cells compared to control cells. However, prior treatment with glycyrrhizin attenuated the TMAOinduced cellcell junction proteins disruption. In addition, TMAO induced the HMGB1 expression through TLR4 signalling pathway in endothelial cells. In in vivo studies, C57BL/6J wild mice were treated with 3 % choline chloride in drinking water to produce enhanced TMAO levels in plasma. Real time PCR analysis showed that HMGB1, TLR4 and inflammatory markers (ICAM & VCAM) were significantly increased in carotid arteries of choline treated mice compared to control mice. In addition, it was also found that collagen I and III expression (fibrotic markers) were significantly increased in carotid arteries of choline treated mice. In conclusion, our results suggested that TMAO modulated endothelial cells phenotype via activating HMGB1 associated TLR4 signalling pathway.Support or Funding Informationsupported by NIH grant, DK104031This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
