Expression of Sirt1 in Choroidal Neovascular Membranes

Lin

Experimental and Therapeutic Medicine

2015

Diabetic retinopathy (DR) is a chronic microvascular complication of diabetes that may lead to loss of vision. The pathogenesis of DR is complex and elevated expression levels of T helper (Th)17 cells and interleukin (IL)-17 have been suggested to be associated with the development and progression of DR. Sirtuin 1 (SIRT1) is a nicotinamide-adenine dinucleotide-dependent histone deacetylase that is downregulated in patients with DR. Previous studies have demonstrated that SIRT1 is capable of inhibiting the production of IL-17. In the present study, 19 patients with proliferative diabetic retinopathy (PDR) and 20 non-diabetic controls with idiopathic macular epiretinal membranes were recruited and the SIRT1 expression levels of excised specimens were analyzed using immunohistochemistry. IL-17 expression levels in the sera from patients with PDR and controls were determined by enzyme-linked immunosorbent assay (ELISA). Furthermore, SIRT1 mRNA and protein expression levels in peripheral blood mononuclear cells (PBMCs) from the two groups were analyzed following culture with or without a SIRT1 activator, resveratrol. IL-17 expression levels in the supernatants of PBMCs were determined using ELISA and the results demonstrated that IL-17 expression levels were increased in the sera of patients with PDR, as compared with the controls. Furthermore, increased expression levels of SIRT1 and IL-17 were detected in fibrovascular membranes and PBMCs harvested from patients with PDR, respectively. Notably, SIRT1 mRNA and protein expression levels were decreased in the PBMCs of patients with PDR and IL-17 production was inhibited following SIRT1 activation. The results of the present study indicated that imbalanced IL-17 and SIRT1 expression levels may contribute to the pathogenesis of DR, and SIRT1 may have a protective role in PDR by inhibiting the production of IL-17.

Section: Discussionsupporting

confidence: 91%

Protective effects of SIRT1 in patients with proliferative diabetic retinopathy via the inhibition of IL-17 expression

Lin

Experimental and Therapeutic Medicine

2015

“…Whilst it appears evident that SIRT1 is crucial for maintaining integrity and function of RPE cells under oxidative stress and chronic inflammation, results about the role of SIRT1 during neovascularization are controversial [45,46]. In fact, a previous study, observing higher SIRT1 expression level in choroidal neovascularization (CNV) membranes than in healthy donor eyes, demonstrated that SIRT1 inhibition with nicotinamide decreased the secretion of proangiogenic factors, such as VEGF-A, platelet-derived growth factor BB and angiogenin in ARPE-19 cells [47]. By contrast, others revealed that treatment with resveratrol, a natural SIRT1 activator, restored VEGF secretion in RPE cells upon oxidative and inflammatory conditions [48].…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Restores LINE-1 Methylation Levels by Modulating SIRT1 and DNMTs Functions in Cellular Models of Age-Related Macular Degeneration

Maugeri¹,

Barchitta²,

Mazzone³

et al. 2018

Preprint

The role of epigenetic alterations in the pathogenesis of age-related macular degeneration (AMD) has been pending so far. Our study investigated the effect of oxidative stress and inflammation on DNA methyltransferases (DNMTs) and Sirtuin 1 (SIRT1) functions, as well as on long interspersed nuclear element-1 (LINE-1) methylation, in human retinal pigment epithelial (ARPE-19) cells. Therefore, we evaluated whether treatment with resveratrol may restore changes in LINE-1 methylation by modulating DNMTs and SIRT1 functions. Cells were treated with 25 mU/ml glucose oxidase (GOx) or 10 µg/ml lipopolysaccharide (LPS) to mimic oxidative or inflammatory conditions, respectively. Oxidative stress decreased DNMT1, DNMT3a, DNMT3b and SIRT1 expression (p-values <0.05), as well as total DNMTs (-28.5%; p<0.0001) and SIRT1 (-29.0%;p<0.0001) activities. Similarly, inflammatory condition decreased DNMT1 and SIRT1 expression (p-values<0.05), as well as total DNMTs (-14.9%;p=0.007) and SIRT1 (-20.1%;p<0.002) activities. Interestingly, GOx- and LPS-treated cells exhibited lower LINE-1 methylation compared to controls (p-values<0.0001). We also demonstrated that treatment with 10 μM resveratrol for 24 hours counteracted the detrimental effect on LINE-1 methylation via increasing DNMTs and SIRT1 functions in cells upon oxidative and inflammatory conditions. However, further studies should explore the perspectives of resveratrol as a suitable strategy for the prevention and/or treatment of AMD.

“…There are an increasing number of papers assessing the relationship between SIRT1 and AMD in animal and in vitro studies. 17,18,42 rs12778366 located in the promoter region of SIRT1 gene and has been studied in the schizophrenia, type 2 diabetes, systemic lupus erythematosus, glucose tolerance, and longevity patients. 20,25,43,44 Lots of studies showed rs12778366 is a possible functional SNP in SIRT1 gene.…”

Section: Discussionmentioning

confidence: 99%

“…They found SIRT1 levels elevated in human choroidal neovascularization membranes compared with control eyes. 18 …”

Section: Introductionmentioning

confidence: 99%

Single Nucleotide Polymorphisms of the Sirtuin 1 (SIRT1) Gene are Associated With age-Related Macular Degeneration in Chinese Han Individuals

Chen

Zhai²,

Zhang

et al. 2015

Medicine

To investigate whether 3 variants in sirtuin 1 (SIRT1) gene contributed differently in patients with age-related macular degeneration (AMD) in a Chinese Han population.We conducted a case–control study in a group of Chinese patients with AMD (n = 253) and contrasted the results against a control group (n = 292). Three single nucleotide polymorphisms (SNPs) of SIRT1 gene including rs12778366, rs3740051, and rs4746720 were genotyped using improved multiplex ligase detection reaction. The association between targeted SNPs and AMD was then analyzed by codominant, dominant, recessive, and allelic models.The genotyping data of rs12778366, rs3740051, and rs4746720 revealed significant deviations from Hardy–Weinberg equilibrium tests in the AMD group but not in the control group.We detected significantly differences of rs12778366 allele distribution between 2 groups in recessive and codominant model (P < 0.05). Homozygous carriers of the risk allele C displayed a higher chance of developing AMD (P = 0.036, odds ratio = 3.227; 95% confidence interval: 1.015–10.265).Our study, for the first time, raises the possibility that genetic variations of SIRT1 could be implicated in the pathophysiology of AMD in the Chinese Han population.