Abstract
The intestinal microbe-derived metabolite trimethylamine N-oxide (TMAO) is implicated in the pathogenesis of cardiovascular diseases (CVDs). The molecular mechanisms of how TMAO induces atherosclerosis and CVDs’ progression are still unclear. In this regard, high-mobility group box protein 1 (HMGB1), an inflammatory mediator, has been reported to disrupt cell–cell junctions, resulting in vascular endothelial hyper permeability leading to endothelial dysfunction. The present study tested whether TMAO associated endothelial dysfunction results via HMGB1 activation. Biochemical and RT-PCR analysis showed that TMAO increased the HMGB1 expression in a dose-dependent manner in endothelial cells. However, prior treatment with glycyrrhizin, an HMGB1 binder, abolished the TMAO-induced HMGB1 production in endothelial cells. Furthermore, Western blot and immunofluorescent analysis showed significant decrease in the expression of cell–cell junction proteins ZO-2, Occludin, and VE-cadherin in TMAO treated endothelial cells compared with control cells. However, prior treatment with glycyrrhizin attenuated the TMAO-induced cell–cell junction proteins’ disruption. TMAO increased toll-like receptor 4 (TLR4) expression in endothelial cells. Inhibition of TLR4 expression by TLR4 siRNA protected the endothelial cells from TMAO associated tight junction protein disruption via HMGB1. In conclusion, our results demonstrate that HMGB1 is one of the important mediators of TMAO-induced endothelial dysfunction.
Highlights
Trimethylamine-N-oxide (TMAO) is a novel intestinal microbe-derived metabolite that has been recently associated with different cardiovascular pathologies [1,2,3,4,5]
ZO-2, Occludin, and VE-Cadherin downregulation by TMAO was further confirmed by Western blotting (Figure 1C), suggesting that that TMAO decreased the expression of tight junction proteins
The present study demonstrated a novel mechanism of TMAO-induced endothelial dysfunction
Summary
Trimethylamine-N-oxide (TMAO) is a novel intestinal microbe-derived metabolite that has been recently associated with different cardiovascular pathologies [1,2,3,4,5]. Elevated levels of TMAO in plasma are shown to be associated with increased risk of major cardiovascular diseases (CVDs) in animal-model studies as well as in humans [2,6]. Elevated TMAO levels were correlated with chronic diseases associated with endothelial dysfunction and atherosclerosis as per the novel research studies [7,8,9]. Patients with chronic kidney disease have shown increased TMAO levels in the plasma [10]. Nuclear factor-kappa B (NF-kB) activation and mitogen-activated protein kinase signaling are reported to be involved in TMAO associated pathogenesis [16]. Despite the progress in understanding TMAO associated pathogenesis, the exact mechanism through which TMAO causes atherosclerotic vascular diseases is currently unclear
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