Rosmarinic acid suppresses retinal neovascularization via cell cycle arrest with increase of p21(WAF1) expression.
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.
Kim
Jeong Hun
JH
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.
Lee
Byung Joo
BJ
Kim
Jin Hyoung
JH
Yu
Young Suk
YS
Kim
Min Young
MY
Kim
Kyu-Won
KW
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
D020533:Angiogenesis Inhibitors; D002934:Cinnamates; D050759:Cyclin-Dependent Kinase Inhibitor p21; D053630:Depsides; D000097123:Rosmarinic Acid; C493956:CDKN1A protein, human