Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide, especially in developed countries, and atherosclerosis (AS) is the common pathological basis of many cardiovascular diseases (CVDs) such as coronary heart disease (CHD). The role of the gut microbiota in AS has begun to be appreciated in recent years. Trimethylamine N-oxide (TMAO), an important gut microbe-dependent metabolite, is generated from dietary choline, betaine, and L-carnitine. Multiple studies have suggested a correlation between plasma TMAO levels and the risk of AS. However, the mechanism underlying this relationship is still unclear. In this review, we discuss the TMAO-involved mechanisms of atherosclerotic CVD from the perspective of inflammation, inflammation-related immunity, cholesterol metabolism, and atherothrombosis. We also summarize available clinical studies on the role of TMAO in predicting prognostic outcomes, including major adverse cardiovascular events (MACE), in patients presenting with AS. Finally, since TMAO may be a novel therapeutic target for AS, several therapeutic strategies including drugs, dietary, etc. to lower TMAO levels that are currently being explored are also discussed.
Highlights
Atherosclerosis (AS) and resulting cardiovascular diseases (CVDs) are serious threats to human health (Anderson et al, 1991; Vilahur et al, 2014)
Experiments using carotid artery endothelial cells (CAECs) and wild-type mice with partially ligated carotid arteries showed that Trimethylamine N-oxide (TMAO) significantly induced NLRP3 inflammasome activation and increased caspase-1 activity, IL-1β production, and cell permeability, which contributed to the endothelial injury that initiates AS (Koka et al, 2016; Boini et al, 2017)
Studies on human umbilical vein endothelial cells (HUVECs) demonstrated that TMAO increased monocyte adhesion, which was partly attributed to upregulation of vascular cell adhesion molecule-1 (VCAM-1) expression by activated protein kinase C (PKC) and p-NF-κB (Ma et al, 2017)
Summary
Atherosclerosis (AS) and resulting cardiovascular diseases (CVDs) are serious threats to human health (Anderson et al, 1991; Vilahur et al, 2014). Studies showed that increased TMAO level induced the activation of NF-kappa B (NF-κB) pathway and increased the expression of pro-inflammatory genes including inflammatory cytokines, adhesion molecules and chemokines (Seldin et al, 2016; Ma et al, 2017). In human clinical studies, elevated TMAO levels were associated with increased risk of AS and CVD (Wang et al, 2011; Koeth et al, 2013; Stubbs et al, 2016). Prospective cohort studies have shown that increased plasma TMAO levels predicted an elevated risk of major adverse cardiovascular events (MACE) such as MI, stroke or death (Tang et al, 2013; Tang et al, 2014; Wang et al, 2014; Li et al, 2017; Li et al, 2019). This article reviews the relationship between gut microbe-dependent TMAO and AS from the perspective of the mechanism including inflammation, inflammation-related immunity, cholesterol metabolism, and atherothrombosis, and its potential for clinical prognostic and as therapeutic target
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