Abstract
Several studies have reported a strong association between high plasma level of trimethylamine N-oxide (TMAO) and atherosclerosis development. However, the exact mechanism underlying this correlation is unknown. In the present study, we try to explore the impact of TMAO on endothelial dysfunction. After TMAO treatment, human umbilical vein endothelial cells (HUVECs) showed significant impairment in cellular proliferation and HUVECs-extracellular matrix (ECM) adhesion compared with control. Likewise, TMAO markedly suppressed HUVECs migration in transwell migration assay and wound healing assay. In addition, we found TMAO up-regulated vascular cell adhesion molecule-1 (VCAM-1) expression, promoted monocyte adherence, activated protein kinase C (PKC) and p-NF-κB. Interestingly, TMAO-stimulated VCAM-1 expression and monocyte adherence were diminished by PKC inhibitor. These results demonstrate that TMAO promotes early pathological process of atherosclerosis by accelerating endothelial dysfunction, including decreasing endothelial self-repair and increasing monocyte adhesion. Furthermore, TMAO-induced monocyte adhesion is partly attributable to activation of PKC/NF-κB/VCAM-1.
Highlights
Cardiovascular disease (CVD) is the major cause of morbidity and mortality worldwide, with growing incidence in developing countries [1,2]
We firstly investigated the effect of trimethylamine N-oxide (TMAO) on cell viability
Atherosclerotic CVD is initiated by vascular endothelial cell (EC) injury, which is frequently linked with endothelial dysfunction [29]
Summary
Cardiovascular disease (CVD) is the major cause of morbidity and mortality worldwide, with growing incidence in developing countries [1,2]. Plasma TMAO is a metabolite of the dietary lipid phosphatidylcholine. TMAO was initially identified as a predictor of cardiovascular risk using a metabolomics approach in a large, independent, clinical cohort study [4,5,6]. Elevated TMAO level in patients with heart failure is positively correlated with prognosis and long-term mortality risk [7,8]. Dietary TMAO was shown to promote up-regulation of multiple macrophage scavenger receptors associated with atherosclerosis and to enhance development of atherosclerotic lesions in mice [6]. The same mechanistic correlation was found in humans [9] These studies provide convincing evidence that TMAO is a strong risk factor for the development of atherosclerosis
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