Abstract 4142242: Phenylacetylglutamine accelerated endothelial senescence and early-stage atherosclerosis formation by modulating cholesterol synthesis

Background: Early-onset acute coronary syndrome (EO-ACS) poses a significant health burden, necessitating a deeper understanding of its underlying mechanisms. Dysfunction or loss of endothelial cells is an early detectable change and contributes to the onset of atherosclerosis. This study aimed to investigate the role of PAGln, in early-onset ACS, endothelial dysfunction, and atherosclerosis progression. Results: Plasma metabolic signatures were measured with untargeted metabolomics in patients with EO-ACS and control subjects. The potential role of PAGln and PAGly, a homologous metabolite of PAGln, in atherosclerosis was evaluated in ApoE −/− mice through PAGln or PAGly supplementation via i.p. injection. Various functional experiments involving PAGln treatment were performed on HUVECs or HAECs to unravel the underlying mechanism. Methods: Elevated levels of circulating PAGln were found to be increased in patients with EO-ACS and positively associated with endothelial chemokine levels. PAGln and PAGly treatment were observed to promote the initiation of atherosclerotic lesion formation in the early-stage and accelerate endothelial senescence. In vitro experiments demonstrated that increased cholesterol synthesis in endothelial cells mediated PAGln-induced endothelial senescence. Conversely, inhibition of cholesterol synthesis alleviated PAGln-induced acceleration of endothelial senescence and delayed the natural aging process of endothelial cells. Conclusion: This study further provide evidence to the detrimental impact of elevated PAGln levels on cardiovascular dysfunction, thus offering valuable insights into the mechanisms underlying early-onset ACS and endothelial senescence.