title: Sac-0601 prevents retinal vascular leakage in a mouse model of diabetic retinopathy.
abstract: Endothelium integrity is important for the normal functioning of vessels, the disruption of which can lead to disease. The blood-retinal barrier required for normal retinal function is compromised in diabetic retinopathy, causing retinal vascular leakage. Previously, we demonstrated the ability of Sac-0601[((2R,3S)-3-acetoxy-6-((3S,10R,13R,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxy)-3,6-dihydro-2H-pyran-2-yl)methyl acetate], a pseudo-sugar derivative of cholesterol, to increase survival of retinal endothelial cells. In the present study, we evaluated the ability of Sac-0601 to prevent retinal vascular leakages in vitro and in vivo. Sac-0601 treatment blocked VEGF-induced formation of actin stress fibers and stabilized the cortical actin ring in retinal endothelial cells. It also inhibited degradation of occludin, an important tight junction protein, and blocked VEGF-induced disruption of its linear pattern at the cell border. The [(14)C] sucrose permeability assay demonstrated that Sac-0601 was able to prevent VEGF-induced retinal endothelial permeability. The compound inhibited the vascular leakage in retina of mice intravitreally injected with VEGF. And it also significantly reduced the leakage in retina of diabetic retinopathy mice model. Taken together, our findings suggest the potential therapeutic usefulness of Sac-0601 for retinal vascular permeability diseases.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120–749, Republic of Korea.
authors.forename: Sony
authors.initials: S
authors.lastname: Maharjan
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.forename: Vijayendra
authors.initials: V
authors.lastname: Agrawal
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Maeng
authors.forename: Kyeojin
authors.initials: K
authors.lastname: Kim
authors.forename: Nam-Jung
authors.initials: NJ
authors.lastname: Kim
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D003930:Diabetic Retinopathy / Q000150:complications*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D062793:Occludin; D010616:Phenanthrenes / Q000494:pharmacology*; D011714:Pyrans / Q000494:pharmacology*; D012171:Retinal Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D014652:Vascular Diseases / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D010616:Phenanthrenes; D011714:Pyrans; C558856:Sac-0601; D042461:Vascular Endothelial Growth Factor A