A prominent feature of inflammatory diseases is endothelial dysfunction. Factors associated with endothelial dysfunction include proinflammatory cytokines, adhesion molecules, and matrix degrading enzymes. At the transcriptional level, they are regulated by the histone deacetylase sirtuin (SIRT) 1 via its actions on the proinflammatory transcription factor nuclear factor- B (NF- B). The role of SIRT6, also a histone deacetylase, in regulating inflammation in endothelial cells is not known. The aim of this study was to determine the effect of SIRT6 knockdown on inflammatory markers in human umbilical vein endothelial cells (HUVECs) in the presence of lipopolysaccharide (LPS). LPS decreased expression of SIRT6 in HUVECs. Knockdown of SIRT6 increased the expression of proinflammatory cytokines (IL-1 , IL-6, IL-8), COX-prostaglandin system, ECM remodelling enzymes (MMP-2, MMP-9 and PAI-1), the adhesion molecule ICAM-1, and proangiogenic growth factors VEGF and FGF-2; cell migration; cell adhesion to leukocytes. Loss of SIRT6 increased the expression of NF- B, whereas overexpression of SIRT6 was associated with decreased NF- B transcriptional activity. Taken together, these results demonstrate that the loss of SIRT6 in endothelial cells is associated with upregulation of genes involved in inflammation, vascular remodelling, and angiogenesis. SIRT6 may be a potential pharmacological target for inflammatory vascular diseases. 1. Introduction Endothelial dysfunction is associated with vasoconstriction, a proinflammatory state, and prothrombotic properties. A number of diseases, including most forms of cardiovascular disease, diabetes, cancer, rheumatoid arthritis, and aging, are associated with endothelial dysfunction [1–3]. Endothelial dysfunction is also a characteristic of bacterial sepsis [4, 5]. To reduce or prevent the high incidence of morbidity and mortality associated with vascular complications, it is essential to understand further the mechanism by which inflammation regulates endothelial function. Systemic inflammation causes an upregulation of a wide number of factors that lead to severe injury of vascular endothelial cells [6–10]. These include growth factors (basic fibroblast growth factor (bFGF or FGF-2), vascular endothelial growth factor (VEGF)); proinflammatory cytokines (IL-1 , IL-6) and chemokines (IL-8); extracellular matrix (ECM) degrading enzymes (plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinases (MMPs)); cell adhesion molecules (intercellular adhesion molecule (ICAM-1), vascular cell adhesion protein (VCAM)-1,
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