Role of Trimethylamine-N-oxide in endothelial dysfunction

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Project Summary Cardiovascular diseases (CVDs) are implicated in 50% of deaths in developed countries and is thus a major health concern and we still remain far from a cure. In addition to the traditional risk factors for CVDs, the influence exerted by gut microbial metabolites on the pathogenesis of CVDs has been recognized only in recent times. Trimethylamine-N-oxide (TMAO), a gut microbe-derived metabolite of dietary phosphatidylcholine/carnitine is elevated in the circulation of CVD patients and has been associated with atherosclerosis and CVD progression in rodents and humans. The present grant proposal attempts to define novel molecular signaling mechanisms mediating the responses of arterial endothelial cells (ECs) to TMAO, which will provide new insights into the pathogenesis of endothelial dysfunction and vascular injury associated with atherosclerosis. Our preliminary results have shown that TMAO induced Nlrp3 inflammasomes have direct actions on the endothelial cells. Thus TMAO induces both inflammatory and non-inflammatory effects leading to endothelial dysfunction and ultimately atherosclerosis. These represents novel pathogenic mechanisms of TMAO beyond inflammation. Based on these observations, we hypothesize that gut microbial metabolites such as TMAO which are released into the circulation act as endogenous danger signals and induce both inflammatory and non-inflammatory responses leading to endothelial dysfunction and vascular injury which consequently manifests into atherogenesis in the arterial wall. To test this hypothesis, we will address how TMAO induces endothelial dysfunction and atherosclerosis in in vivo using Nlrp3-/- mice, endothelium-specific Nlrp3 knockout mice (EC-Nlrp3-/-) and their wild type littermates. We will then investigate the non-inflammatory effects of TMAO leading to endothelium dependent vasodilation, pyroptosis and DAMPs production both in vitro and in vivo. Lastly, we will explore the novel molecular signaling pathways mediating TMAO-induced endothelial exosome release leading to endothelial dysfunction and vascular injury. The proposed studies will reveal new mechanistic insights of CVD pathogenesis induced by microbial metabolites such as TMAO and will pave way to the development of clinically relevant, novel therapeutic strategies for treating atherosclerosis and resulting CVDs.