Anti-Inflammatory Properties of Sirtuin 6 in Human Umbilical Vein Endothelial Cells

Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, VIC 3084, Australia
Mediators of Inflammation (Impact Factor: 2.42). 10/2012; 2012:597514. DOI: 10.1155/2012/597514
Source: PubMed

ABSTRACT 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-κB (NF-κB). 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-1β, 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-κB, whereas overexpression of SIRT6 was associated with decreased NF-κB 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.

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    ABSTRACT: The most common feature of endothelial dysfunction is endothelial inflammation. A bunch of factors are associated with endothelial dysfunction. These include pro-inflammatory cytokines, cell adhesion molecules, and matrix degrading enzymes. SIRT4, a member of the sirtuin family, is a mitochondrial ADP-ribosyltransferase. The roles of SIRT4 in regulating inflammation in endothelial cells are unknown. In this study, we found that lipopolysaccharide treatment decreased the expression of SIRT4 in human umbilical vein endothelial cells. Silence of SIRT4 exacerbated the expression of pro-inflammatory cytokines (IL-1β, IL-6 and IL-8), COX-prostaglandin system (COX-2), ECM remodeling enzymes MMP-9, and the adhesion molecule ICAM-1. The upregulation of these genes are involved in inflammation, vascular remodeling, and angiogenesis. In contrast, overexpression of SIRT4 attenuated the induction of these factors. Mechanistically, SIRT4 was found to interfere with the NF-κB signaling pathway by preventing NF-κB nuclear translocation and thereby has an anti-inflammatory function. Loss of SIRT4 increased the nuclear translocation as well as the transcriptional activity of NF-κB. However, overexpression of SIRT4 mitigated the nuclear translocation and the transcriptional activity of NF-κB. Our data suggested that SIRT4 might be a potential pharmacological target for inflammatory vascular diseases.
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