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Antiangiogenic mechanisms of simvastatin in retinal endothelial cells

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Abstract

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 [3H]-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.

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Acknowledgments

We acknowledge David Goodman (Pharmascience), Waichiro Katsuda, Tomoko Saeki, and Noriyuki Yoshida (Aqumen Biopharmaceuticals, K.K.) for their excellent help. The study was supported in part by grants from the Ministry of Education, Science, Sports and Culture, Japan (Grant-in-Aid for Scientific Research #21592233).

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Authors and Affiliations

  1. Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan

    Yasuaki Hata, Muneki Miura, Ryo Asato, Takeshi Kita, Kumiyo Oba, Shuhei Kawahara, Ryoichi Arita, Ri-ichiro Kohno, Shintaro Nakao & Tatsuro Ishibashi

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  1. Yasuaki Hata
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  2. Muneki Miura
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  3. Ryo Asato
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  4. Takeshi Kita
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  5. Kumiyo Oba
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  6. Shuhei Kawahara
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  7. Ryoichi Arita
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  8. Ri-ichiro Kohno
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  9. Shintaro Nakao
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  10. Tatsuro Ishibashi
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Correspondence to Yasuaki Hata.

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Hata, Y., Miura, M., Asato, R. et al. Antiangiogenic mechanisms of simvastatin in retinal endothelial cells. Graefes Arch Clin Exp Ophthalmol 248, 667–673 (2010). https://doi.org/10.1007/s00417-009-1282-4

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  • DOI: https://doi.org/10.1007/s00417-009-1282-4

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