Potent Inhibition of Cicatricial Contraction in Proliferative Vitreoretinal Diseases by Statins
- Shuhei Kawahara1,
- Yasuaki Hata, PhD (hatachan{at}med.kyushu-u.ac.jp)1,
- Takeshi Kita, PhD1,
- Ryoichi Arita1,
- Muneki Miura, PhD1,
- Shintaro Nakao, PhD2,
- Yasutaka Mochizuki, PhD1,
- Hiroshi Enaida, PhD1,
- Tadahisa Kagimoto3,
- Yoshinobu Goto, PhD4,
- Ali Hafezi-Moghadam, PhD2 and
- Tatsuro Ishibashi, PhD1
- 1Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan
- 2Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 325 Cambridge Street, 3rd Floor Boston, MA 02114, USA
- 3Aqumen Biopharmaceuticals K.K., 2-3-36-403 Tenjin, Chuo-Ku, Fukuoka 810-0001, Japan
- 4Department of Occupational Therapy, Faculty of Rehabilitation, International University of Health and Welfare at Okawa, 137-1 Enokizu, Okawa, Fukuoka 831-8501, Japan
Abstract
Objective: In spite of tremendous progress in vitreoretinal surgery, certain post-surgical complications limit the success in the treatment of proliferative vitreoretinal diseases (PVD), such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). One of the most significant complications is the cicatricial contraction of proliferative membranes, resulting in tractional retinal detachment and severe vision loss. Novel pharmaceutical approaches are thus urgently needed for the management of these vision-threatening diseases. In the current study, we investigated the inhibitory effects of statins on the progression of PVD.
Research Design and Methods: Human vitreous concentrations of TGF-β2 were measured by ELISA. TGF-β2- and vitreous-dependent phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase pathway, and collagen gel contraction simulating cicatrical contraction were analyzed using cultured hyalocytes. Inhibitory effects of simvastatin on cicatrical contraction were assessed both in vitro and in vivo.
Results: Human vitreous concentrations of TGF-β2 were significantly higher in the samples from patients with PVD compared to those with non-PVD. Simvastatin inhibited TGF-β2-dependent MLC phosphorylation and gel contraction in a dose- and time-dependent manner, and was capable of inhibiting translocation of Rho protein to the plasma membrane in the presence of TGF-β2. Vitreous samples from patients with PVD enhanced MLC phosphorylation and gel contraction, while simvastatin almost completely inhibited these phenomena. Finally, intravitreal injection of simvastatin dose-dependently prevented the progression of diseased states in an in vivo model of PVR.
Conclusions: Statins might have therapeutic potential in the prevention of PVD.
Footnotes
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- Received March 2, 2007.
- Accepted June 26, 2008.
- Copyright © American Diabetes Association
