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Arul J Duraisamy - Top 30 Publications

Sirt1- A Guardian of the Development of Diabetic Retinopathy.

Diabetic retinopathy is a multifactorial disease, and the exact mechanism of its pathogenesis remains obscure. A multifunctional deacetylase Sirtuin 1 (Sirt1), is implicated in regulation of many cellular functions and transcription of genes, and retinal Sirt1 is inhibited in diabetes. Our aim is to determine the role of Sirt1 in the development of diabetic retinopathy, and elucidate the molecular mechanism of its downregulation. Using mice overexpressing Sirt1, diabetic for 8 month, structural, functional and metabolic abnormalities were investigated in vascular and neuronal retina. The role of epigenetics in Sirt1 transcriptional suppression was investigated in the retinal microvessels. Compared to wildtype diabetic mice, retinal vasculature from Sirt1 diabetic mice did not present any increase in the number of apoptotic cells, degenerative capillaries and decrease in vascular density. Sirt1 diabetic mice were also protected from mitochondrial damage, and they had normal ERG responses and ganglion cell layer thickness. Wildtype diabetic mice had Sirt1 promoter DNA hypermethylated, which was alleviated in Sirt1 diabetic mice, suggesting the role of epigenetics in its transcriptional suppression. Thus, strategies targeting amelioration of Sirt1 inhibition have potential to maintain retinal vascular and neuronal homeostasis, providing opportunities to retard the development of diabetic retinopathy in its early stages.

Crosstalk Between Histone and DNA Methylation in Regulation of Retinal Matrix Metalloproteinase-9 in Diabetes.

Diabetes activates matrix metalloproteinase-9 (MMP-9), and MMP-9 via damaging retinal mitochondria, activates capillary cell apoptosis. MMP-9 promoter has binding sites for many transcription factors, and in diabetes its promoter undergoes epigenetic modifications, including histone modifications and DNA methylation. Enhancer of Zeste homolog 2 (Ezh2), which catalyzes dimethylation/trimethylation of histone 3 lysine 27 (H3K27me2 and me3), is also associated with DNA methylation. Our aim was to investigate link(s) between histone and DNA modifications in the regulation of MMP-9.