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 hyperglycaemia, typical features of metabolic diseases, trigger endothelial damage and release of E-selectin, a marker of endothelial activation. In the present study, we investigated molecular pathways involved in the regulation of endothelial cell activation induced by tumour necrosis factor-α (TNF-α) and high glucose. In cultured human umbilical vein endothelial cells (HUVECs), we studied the role of HuR, an ELAV (embryonic lethal, abnormal vision, Drosophila) family RNA-binding protein, and Sirtuin 1 (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 blood mononuclear cells (PBMCs) of subjects with and without the metabolic syndrome (MS), by immunoprecipitation (IP) of the ribonucleoprotein (RNP) complex. We found that SIRT1 overexpression prevented TNF-α- and high-glucose-dependent nuclear factor-κB (NF-κB)-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 MS compared with 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 hyperglycaemia-induced E-selectin release and endothelial cell activation. Therefore, increasing SIRT1 expression represents a strategy to counter the accelerated vascular disease in metabolic disorders.
*Department of Medicine-DIMED, University of Padova, Padova, Italy.
Giulio
G
Ceolotto
*Department of Medicine-DIMED, University of Padova, Padova, Italy.
Saula Vigili
SV
De Kreutzenberg
*Department of Medicine-DIMED, University of Padova, Padova, Italy.
Arianna
A
Cattelan
†Department of Clinical Pathology, Regional Center for Diagnostic, Prognostic and Predictive Biomarkers, ULSS 12, Venezia, Italy.
Aline S C
AS
Fabricio
†Department of Clinical Pathology, Regional Center for Diagnostic, Prognostic and Predictive Biomarkers, ULSS 12, Venezia, Italy.
Elisa
E
Squarcina
†Department of Clinical Pathology, Regional Center for Diagnostic, Prognostic and Predictive Biomarkers, ULSS 12, Venezia, Italy.
Massimo
M
Gion
*Department of Medicine-DIMED, University of Padova, Padova, Italy.
Andrea
A
Semplicini
*Department of Medicine-DIMED, University of Padova, Padova, Italy.
Gian Paolo
GP
Fadini
*Department of Medicine-DIMED, University of Padova, Padova, Italy.
Angelo
A
Avogaro
D000107:Acetylation; D000268:Adhesiveness; D001549:Benzamides / Q000494:pharmacology; D002448:Cell Adhesion; D019040:E-Selectin / Q000378:metabolism / Q000502:physiology*; D051959:ELAV Proteins / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009284:Naphthols / Q000494:pharmacology; D055550:Protein Stability; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D001549:Benzamides; D019040:E-Selectin; D051959:ELAV Proteins; D016328:NF-kappa B; D009284:Naphthols; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; C439060:sirtinol; D056564:Sirtuin 1; D005947:Glucose; D000077185:Resveratrol