Sirtuin 1 stabilization by HuR represses TNF-α and glucose induced E-Selectin release and endothelial cell adhesiveness in vitro. Relevance to human metabolic syndrome.

Chronic inflammation and hyperglycemia, typical features of metabolic diseases, trigger endothelial damage and release of E-selectin, a marker of endothelial activation.Herein, we investigated molecular pathways involved in the regulation of endothelial cell activation induced by TNF-α and high glucose. In cultured HUVECs, we studied the role of HuR, an ELAV family RNA-binding protein, and SIRT1 on E-Selectin release and cell adhesion at different glucose concentrations. HuR expression and binding to SIRT1 were also analysed ex-vivo in peripheral mononuclear cells (PBMCs) of subjects with and without metabolic syndrome (MS), by immunoprecipitation of the ribonucleoprotein complex. We found that SIRT1 overexpression prevented TNFα- and high glucose-dependent NF-kB-p65 acetylation, E-Selectin promoter activity, E-Selectin release and adhesion of THP-1 cells to HUVECs. The same was mimicked by HuR overexpression, which binds and stabilizes SIRT1 mRNA. Importantly, in PBMCs of individuals with the MS compared to those without, SIRT1 expression was lower, and the ability of HuR to bind SIRT1 mRNA was significantly reduced, while plasma E-selectin was increased. We conclude that post-transcriptional stabilization of SIRT1 by HuR represses inflammation- and hyperglycemia-induced E-Selectin release and endothelial cell activation. Therefore, increasing SIRT1 expression represents a strategy to counter the accelerated vascular disease in metabolic disorders