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Sampathkumar Rangasamy, Arup Das, Paul McGuire; Epigenetic Alterations of Endothelial Cell Junction Molecules: Role of Metabolic Memory in the Development of Diabetic Macular Edema. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5408.
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© ARVO (1962-2015); The Authors (2016-present)
Data from recent clinical studies (EDIC) suggest that the effect of tight control of blood glucose in the early stages prevents the complications of diabetic retinopathy. Previous exposure to poor glycemic control despite subsequent normalization of blood glucose leads to epigenetic modifications (metabolic memory) and the development of diabetic complications. The aim of the present study was to determine whether epigenetic changes occur in diabetic animals that affect endothelial cell junction molecules mediating normal vascular permeability.
Human retinal microvascular endothelial cells (HREC) were treated with high glucose (30.5 mM) for 7 days. A ChIP-based assay was developed to examine the methylation/acetylation state of the VE-cadherin and Occludin genes. The retinal endothelial vascular permeability was measured using ECIS (Electric Cell-substrate Impedance Sensing). The expression of mRNAs was done by real time PCR analysis.
RNA and protein expression of VE-cadherin and Occludin molecules were significantly reduced in the retinal microvasculature of diabetic animals. HRECs exposed to high glucose down regulate VE-cadherin and Occludin and this status is maintained for several days following the returning to a normal level of glucose. Interestingly, the "metabolic memory’ phenomena were demonstrated through the persistent loss of VE-cadherin molecule even after returning to normoglycemic conditions. This change is further associated with a functional loss of endothelial barrier resistance. Chip study revealed that the K9 residues of H3 histones within specific regions of the promoter are more highly methylated compared to histones in the same regions of control cells.
The alteration of junctional protein levels is an important mechanism in the development of diabetic retinopathy that can be affected by the metabolic memory phenomenon. Hence, therapeutic targeting of the epigenetic mechanisms involved in the modification of cell junction protein expression may serve as a potentially new therapeutic strategy in the management of diabetic macular edema.
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