title: Rosmarinic acid suppresses retinal neovascularization via cell cycle arrest with increase of p21(WAF1) expression.
abstract: Pathological angiogenesis is the most common cause of blindness at all ages including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Despite advances in therapy, retinopathy of prematurity remains the most sight-threatening vaso-proliferative retinopathy in children. Herein, we demonstrated that rosmarinic acid has an anti-angiogenic activity to retinal neovascularization in a mouse model of retinopathy of prematurity, which is related to cell cycle arrest with increase of p21(WAF1). Rosmarinic acid significantly inhibited the proliferation of retinal endothelial cells in a dose-dependent manner, and inhibited in vitro angiogenesis of tube formation. Interestingly, the anti-proliferative activity of rosmarinic acid on retinal endothelial cells was related to G2/M phase cell cycle arrest in a dose-dependent manner. With treatment of rosmarinic acid, retinal endothelial cells in G2/M phase increased whereas those in G0/G1 and S phases decreased, which was accompanied by increase of p21(WAF1) expression in a dose-dependent manner. Moreover, rosmarinic acid effectively suppressed retinal neovascularization in a mouse model of retinopathy of prematurity, and showed no retinal toxicity. These data suggest rosmarinic acid could be a potent inhibitor of retinal neovascularization and may be applied in the treatment of other vasoproliferative retinopathies.
authors.affiliation: Department of Ophthalmology, College of Medicine, Seoul National University & Seoul Artificial Eye Center Clinical Research Institute, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Byung Joo
authors.initials: BJ
authors.lastname: Lee
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Kim
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Yu
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002934:Cinnamates / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D053630:Depsides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D008810:Mice, Inbred C57BL; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000097123:Rosmarinic Acid
chemical_list: D020533:Angiogenesis Inhibitors; D002934:Cinnamates; D050759:Cyclin-Dependent Kinase Inhibitor p21; D053630:Depsides; D000097123:Rosmarinic Acid; C493956:CDKN1A protein, human