title: Overexpression of Bcl-2 in vascular endothelium inhibits the microvascular lesions of diabetic retinopathy.
abstract: Recent studies on the pathogenesis of diabetic retinopathy have focused on correcting adverse biochemical alterations, but there have been fewer efforts to enhance prosurvival pathways. Bcl-2 is the archetypal member of a group of antiapoptotic proteins. In this study, we investigated the ability of overexpressing Bcl-2 in vascular endothelium to protect against early stages of diabetic retinopathy. Transgenic mice overexpressing Bcl-2 regulated by the pre-proendothelin promoter were generated, resulting in increased endothelial Bcl-2. Diabetes was induced with streptozotocin, and mice were sacrificed at 2 months of study to measure superoxide generation, leukostasis, and immunohistochemistry, and at 7 months to assess retinal histopathology. Diabetes of 2 months duration caused a significant decrease in expression of Bcl-2 in retina, upregulation of Bax in whole retina and isolated retinal microvessels, and increased generation of retinal superoxide and leukostasis. Seven months of diabetes caused a significant increase in the number of degenerate (acellular) capillaries in diabetic animals. Furthermore, overexpression of Bcl-2 in the vascular endothelium inhibited the diabetes-induced degeneration of retinal capillaries and aberrant superoxide generation, but had no effect on Bax expression or leukostasis. Therefore, overexpression of Bcl-2 in endothelial cells inhibits the capillary degeneration that is characteristic of the early stages of diabetic retinopathy, and this effect seems likely to involve inhibition of oxidative stress.
authors.affiliation: Center for Diabetes Research, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA. tsk@case.edu
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Du
authors.forename: Casey M
authors.initials: CM
authors.lastname: Miller
authors.forename: Denise A
authors.initials: DA
authors.lastname: Hatala
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Levin
mesh_terms: D000818:Animals; D017209:Apoptosis; D002196:Capillaries / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000196:embryology; D005786:Gene Expression Regulation; D007150:Immunohistochemistry / Q000379:methods; D018921:Leukostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D013481:Superoxides