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: 3.24). 10/2012; 2012(10):597514. DOI: 10.1155/2012/597514
Source: PubMed


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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Available from: Martha Lappas, Oct 02, 2015
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    • "Alternatively, oxidative stress may regulate Sirt6 expression and function via other posttranslational modifications of the protein, reduction of the level of NAD+, or inhibition of Sirt6 transcription and translation similar to previously described mechanisms regulating Sirt1 function [41]. Future studies are needed to address these possibilities and investigate whether oxidative stress is involved in loss of Sirt6 expression and function in cancer, cardiomyocyte hypotrophy, and inflammation [25, 33, 42]. "
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    ABSTRACT: Accumulating evidence has shown that diabetes accelerates aging and endothelial cell senescence is involved in the pathogenesis of diabetic vascular complications, including diabetic retinopathy. Oxidative stress is recognized as a key factor in the induction of endothelial senescence and diabetic retinopathy. However, specific mechanisms involved in oxidative stress-induced endothelial senescence have not been elucidated. We hypothesized that Sirt6, which is a nuclear, chromatin-bound protein critically involved in many pathophysiologic processes such as aging and inflammation, may have a role in oxidative stress-induced vascular cell senescence. Measurement of Sirt6 expression in human endothelial cells revealed that H2O2 treatment significantly reduced Sirt6 protein. The loss of Sirt6 was associated with an induction of a senescence phenotype in endothelial cells, including decreased cell growth, proliferation and angiogenic ability, and increased expression of senescence-associated β-galactosidase activity. Additionally, H2O2 treatment reduced eNOS expression, enhanced p21 expression, and dephosphorylated (activated) retinoblastoma (Rb) protein. All of these alternations were attenuated by overexpression of Sirt6, while partial knockdown of Sirt6 expression by siRNA mimicked the effect of H2O2. In conclusion, these results suggest that Sirt6 is a critical regulator of endothelial senescence and oxidative stress-induced downregulation of Sirt6 is likely involved in the pathogenesis of diabetic retinopathy.
    BioMed Research International 08/2014; 2014:902842. DOI:10.1155/2014/902842 · 3.17 Impact Factor
    • "In the liver, SIRT6 indirectly suppresses gluconeogenesis by deacetylating and activating the GCN5 acetyltransferase, which in turn acetylates and inhibits the metabolic regulator PGC1α (Dominy et al., 2012). SIRT6 suppresses obesity, fatty liver, metabolic syndrome (Kanfi et al., 2010; Kim et al., 2010b; Schwer et al., 2010), inflammation (Lappas, 2012; Lee et al., 2013; Xiao et al., 2012), cardiac hypertrophy (Sundaresan et al., 2012; Yu et al., 2013) and cellular senescence (Cardus et al., 2013; Kawahara et al., 2009; Shen et al., 2013; Xie et al., 2012). SIRT6 also promotes genomic stability by enhancing the activities of key proteins involved in DNA repair, including PARP-1, CtIP and DNA-PK (Kaidi et al., 2010; Mao et al., 2012; McCord et al., 2009; Toiber et al., 2013). "
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    ABSTRACT: In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Despite the inefficiency of ATP generation through glycolysis, the breakdown of glucose into lactate provides cancer cells with a number of advantages, including the ability to withstand fluctuations in oxygen levels, and the production of intermediates that serve as building blocks to support rapid proliferation. Recent evidence from many cancer types supports the notion that pervasive metabolic reprogramming in cancer and stromal cells is a crucial feature of neoplastic transformation. Two key transcription factors that play major roles in this metabolic reprogramming are hypoxia inducible factor-1 (HIF1) and MYC. Sirtuin-family deacetylases regulate diverse biological processes, including many aspects of tumor biology. Recently, the sirtuin SIRT6 has been shown to inhibit the transcriptional output of both HIF1 and MYC, and to function as a tumor suppressor. In this Review, we highlight the importance of HIF1 and MYC in regulating tumor metabolism and their regulation by sirtuins, with a main focus on SIRT6.
    Disease Models and Mechanisms 08/2014; 7(9). DOI:10.1242/dmm.016287 · 4.97 Impact Factor
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    ABSTRACT: Although there are different mechanistic theories for aging,1 endothelial dysfunction (ED) is a rather neglected player in the aging process. A maladaptive insulin/IGF-1-like signaling (IIS) has a remarkable importance in proaging mechanisms, and insulin has direct effects on ED.2 Therefore, we assume that the endothelium plays a key role in mediating the aging process in the presence of maladaptive insulin signaling. This latter condition leads to insulin resistance and affects several aspects involved in premature aging, such as body composition, mitochondrial activity, and endocrine function. The present review highlights key mediators and mechanisms responsible for the link between endothelial dysfunction, insulin resistance and aging. In particular, we discuss the sirtuin-1 system, the p66Shc pathway, telomeres, and their interrelationships with endothelial damage and repair.
    Journal of the American Heart Association 04/2013; 2(3):e000262. DOI:10.1161/JAHA.113.000262 · 4.31 Impact Factor
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