title: Simvastatin inhibits leukocyte accumulation and vascular permeability in the retinas of rats with streptozotocin-induced diabetes.
abstract: Leukocytes play important roles in the pathogenesis of diabetic retinopathy. Recently, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors have been reported to exert various effects in addition to their lipid-lowering ability. We investigated the effects of simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on leukocyte-induced diabetic changes in retinas. Diabetes was induced in Long-Evans rats with streptozotocin, and simvastatin administration was begun immediately after the induction of diabetes. Two weeks of treatment with simvastatin suppressed significantly the number of leukocytes adhering to retinal vessel endothelium and the number of leukocytes accumulated in the retinal tissue by 72.9% and 41.0%, respectively (P < 0.01). The expression of intercellular adhesion molecule-1 (ICAM-1) and the CD18 (the common beta-chain of ICAM-1 ligands) were both suppressed with simvastatin. The amount of vascular endothelial growth factor in the retina was attenuated in the simvastatin-treated group. To evaluate the effects of simvastatin on leukocyte-induced endothelial cell damage, vascular permeability in the retina was measured with fluorescein-labeled dextran. Treatment with simvastatin markedly reduced retinal permeability (P = 0.014). This suggests that simvastatin attenuates leukocyte-endothelial cell interactions and subsequent blood-retinal barrier breakdown via suppression of vascular endothelial growth factor-induced ICAM-1 expression in the diabetic retina. Simvastatin may thus be useful in the prevention of diabetic retinopathy.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Miyahara
authors.forename: Junichi
authors.initials: J
authors.lastname: Kiryu
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamashiro
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Hirose
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tamura
authors.forename: Hideto
authors.initials: H
authors.lastname: Katsuta
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nishijima
authors.forename: Akitaka
authors.initials: A
authors.lastname: Tsujikawa
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Honda
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000096:biosynthesis; D002199:Capillary Permeability / Q000187:drug effects*; D002448:Cell Adhesion; D002450:Cell Communication; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004730:Endothelium, Vascular / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008024:Ligands; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology*; D013311:Streptozocin; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018821:CD18 Antigens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008024:Ligands; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D013311:Streptozocin; D019821:Simvastatin; D019001:Nitric Oxide Synthase