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Potent Inhibition of Cicatricial Contraction in Proliferative Vitreoretinal Diseases by Statins

  1. Shuhei Kawahara1,
  2. Yasuaki Hata1,
  3. Takeshi Kita1,
  4. Ryoichi Arita1,
  5. Muneki Miura1,
  6. Shintaro Nakao2,
  7. Yasutaka Mochizuki1,
  8. Hiroshi Enaida1,
  9. Tadahisa Kagimoto3,
  10. Yoshinobu Goto4,
  11. Ali Hafezi-Moghadam2 and
  12. Tatsuro Ishibashi1
  1. 1Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan
  2. 2Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
  3. 3Aqumen Biopharmaceuticals, Tenjin, Chuo-Ku, Fukuoka, Japan
  4. 4Department of Occupational Therapy, Faculty of Rehabilitation, International University of Health and Welfare at Okawa, Enokizu, Okawa, Fukuoka, Japan
  1. Corresponding author: Yasuaki Hata, hatachan{at}med.kyushu-u.ac.jp

Abstract

OBJECTIVE—Despite tremendous progress in vitreoretinal surgery, certain postsurgical complications limit the success in the treatment of proliferative vitreoretinal diseases (PVDs), 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 PVDs.

RESEARCH DESIGN AND METHODS—Human vitreous concentrations of transforming growth factor-β2 (TGF-β2) were measured by enzyme-linked immunosorbent assay. 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 with those without 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, whereas 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 PVDs.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 3 July 2008.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted June 26, 2008.
    • Received March 2, 2007.
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This Article

  1. Diabetes vol. 57 no. 10 2784-2793
  1. All Versions of this Article:
    1. db08-0302v1
    2. 57/10/2784 most recent