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T. S. Kern, Y. Du, L. A. Levin; Bcl-2, Endothelial Death, and Capillary Degeneration in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3638.
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Apoptosis is believed to be a crucial step in the development of diabetic retinopathy, and Bcl-2 has been found to regulate cellular susceptibility to apoptosis. We studied (1) the effect of diabetes and hyperglycemia on expression of Bcl-2 in retina and retinal endothelial cells, (2) the ability of Bcl-2 to inhibit hyperglycemia-induced death of retinal endothelial cells and degeneration of retinal capillaries in diabetes, and (3) the roles of nitric oxide, cyclooxygenase-2 (COX-2) and caspases on hyperglycemia-induced alterations in Bcl-2 expression.
Nondiabetic and diabetic wildtype mice and transgenic mice overexpressing Bcl-2 selectively in endothelium (using the preproendothelin promoter) were used. For in vitro experiments, primary bovine retinal endothelial cells (BREC) were incubated in 5mM and 25 mM glucose.
In vivo, diabetes decreased Bcl-2 expression in whole retina, increased the rate of endothelial cell death in retinal capillaries, and caused degeneration of retinal capillaries (resulting in acellular capillaries). Diabetes-induced degeneration of retinal capillaries over an 8 month period was inhibited in animals overexpressing Bcl-2 in the endothelium. In vitro findings were consistent with the in vivo studies. Elevated glucose decreased Bcl-2 expression in BREC, and death of BREC in elevated glucose was significantly inhibited by incubating the cells with a peptide containing a cell-permeable, BH4 (anti-apoptotic) domain of Bcl-2. Inhibition of NO production (with L-NAME), COX-2 (with NS-398), or caspases (with BD-FMK) inhibited the decrease in Bcl-2 and increase in cell death due to elevated glucose in vitro.
Diabetes-induced increase in retinal capillary cell death can be inhibited by over-expression of the anti-apoptotic protein Bcl-2. We postulate that Bcl-2 downregulation contributes to the process of retinal vascular cell death and development of retinopathy in diabetes, and that therapies that preserve Bcl-2 will help inhibit the development of diabetic retinopathy.
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