Antiangiogenic mechanisms of simvastatin in retinal endothelial cells

• Published in: Graefe's archive for clinical and experimental ophthalmology Vol. 248; no. 5; pp. 667 - 673
• Main Authors: Hata, Yasuaki, Miura, Muneki, Asato, Ryo, Kita, Takeshi, Oba, Kumiyo, Kawahara, Shuhei, Arita, Ryoichi, Kohno, Ri-ichiro, Nakao, Shintaro, Ishibashi, Tatsuro
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.05.2010; Springer Nature B.V
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Basic Science; Blotting, Western; Cattle; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Medicine; Medicine & Public Health; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Myosin Light Chains - metabolism; Ophthalmology; Phosphorylation; Retinal Vessels - cytology; Simvastatin - pharmacology; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Angiogenesis; Retinal endothelial cells; Mevalonate; Statin; Vascular endothelial growth factor
• ISSN: 0721-832X; 1435-702X
• DOI: 10.1007/s00417-009-1282-4

Background While statins have an anti-angiogenic property, their underlying mechanisms are not fully understood. We investigated intracellular mechanisms of simvastatin-mediated reduction in VEGF-induced signalings. Methods The effects of simvastatin on cell proliferation and viability were evaluated by [ 3 H]-thymidine incorporation in retinal endothelial cells (RECs) and cell counting. The impact of simvastatin on VEGF-induced phosphorylation of p44/42 mitogen-activated protein (MAP) kinase, myosin light chain (MLC), and VEGF-receptor (VEGFR) 2 were examined by Western blotting. Involvement of the mevalonate pathway in VEGF-induced signaling was also examined. Results Simvastatin (1 and 10 µM) suppressed VEGF-induced RECs proliferation in a concentration-dependent manner, without affecting cell viability. Simvastatin significantly inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream mediators, p44/42 MAP kinase and MLC. Mevalonate completely reversed VEGF-induced VEGFR2 phosphorylation, but only partially reversed the phosphorylation of p44/42 MAP kinase and MLC. Conclusion These data indicate that simvastatin exerts its anti-angiogenic effects through the reduction of VEGFR2 phosphorylation in RECs at least in part. However, there seems to be both mevalonate-dependent and independent pathway in simvastatin’s anti-angiogenic property.