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Potent inhibition of cicatricial contraction in proliferative vitreoretinal diseases by statins.

Kawahara S, Hata Y, Kita T, Arita R, Miura M, Nakao S, Mochizuki Y, Enaida H, Kagimoto T, Goto Y, Hafezi-Moghadam A, Ishibashi T - Diabetes (2008)

Bottom Line: In the current study, we investigated the inhibitory effects of statins on the progression of PVDs.Human vitreous concentrations of TGF-beta2 were significantly higher in the samples from patients with PVD compared with those without PVD.Statins might have therapeutic potential in the prevention of PVDs.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.

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-beta2 (TGF-beta2) were measured by enzyme-linked immunosorbent assay. TGF-beta2-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-beta2 were significantly higher in the samples from patients with PVD compared with those without PVD. Simvastatin inhibited TGF-beta2-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-beta2. 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.

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Related in: MedlinePlus

The effect of simvastatin on TGF-β2–induced contraction of hyalocyte-containing collagen gels. Hyalocytes were embedded in type I collagen gels (n = 4). A: After starvation and pretreatment with indicated concentrations of simvastatin for 24 h, the collagen gels were stimulated with 3 ng/ml TGF-β2. Five days after the stimulation, the gels were photographed. B: The diameter of the collagen gels was measured and expressed as a percentage of the average diameter of control group. *P < 0.05; NS, not significant compared with TGF-β2 alone.
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f3: The effect of simvastatin on TGF-β2–induced contraction of hyalocyte-containing collagen gels. Hyalocytes were embedded in type I collagen gels (n = 4). A: After starvation and pretreatment with indicated concentrations of simvastatin for 24 h, the collagen gels were stimulated with 3 ng/ml TGF-β2. Five days after the stimulation, the gels were photographed. B: The diameter of the collagen gels was measured and expressed as a percentage of the average diameter of control group. *P < 0.05; NS, not significant compared with TGF-β2 alone.

Mentions: The control gels showed no apparent contraction up to 5 days, whereas TGF-β2 caused substantial collagen gel contraction in a time-dependent manner in the first 5 days (57.6% vs. control). TGF-β2–dependent collagen gel contraction was significantly reduced by simvastatin starting at a concentration of 1 μmol/l, and the reduction was greater at 3 and 10 μmol/l (92 and 100% vs. control, respectively) (Fig. 3).


Potent inhibition of cicatricial contraction in proliferative vitreoretinal diseases by statins.

Kawahara S, Hata Y, Kita T, Arita R, Miura M, Nakao S, Mochizuki Y, Enaida H, Kagimoto T, Goto Y, Hafezi-Moghadam A, Ishibashi T - Diabetes (2008)

The effect of simvastatin on TGF-β2–induced contraction of hyalocyte-containing collagen gels. Hyalocytes were embedded in type I collagen gels (n = 4). A: After starvation and pretreatment with indicated concentrations of simvastatin for 24 h, the collagen gels were stimulated with 3 ng/ml TGF-β2. Five days after the stimulation, the gels were photographed. B: The diameter of the collagen gels was measured and expressed as a percentage of the average diameter of control group. *P < 0.05; NS, not significant compared with TGF-β2 alone.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551690&req=5

f3: The effect of simvastatin on TGF-β2–induced contraction of hyalocyte-containing collagen gels. Hyalocytes were embedded in type I collagen gels (n = 4). A: After starvation and pretreatment with indicated concentrations of simvastatin for 24 h, the collagen gels were stimulated with 3 ng/ml TGF-β2. Five days after the stimulation, the gels were photographed. B: The diameter of the collagen gels was measured and expressed as a percentage of the average diameter of control group. *P < 0.05; NS, not significant compared with TGF-β2 alone.
Mentions: The control gels showed no apparent contraction up to 5 days, whereas TGF-β2 caused substantial collagen gel contraction in a time-dependent manner in the first 5 days (57.6% vs. control). TGF-β2–dependent collagen gel contraction was significantly reduced by simvastatin starting at a concentration of 1 μmol/l, and the reduction was greater at 3 and 10 μmol/l (92 and 100% vs. control, respectively) (Fig. 3).

Bottom Line: In the current study, we investigated the inhibitory effects of statins on the progression of PVDs.Human vitreous concentrations of TGF-beta2 were significantly higher in the samples from patients with PVD compared with those without PVD.Statins might have therapeutic potential in the prevention of PVDs.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.

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-beta2 (TGF-beta2) were measured by enzyme-linked immunosorbent assay. TGF-beta2-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-beta2 were significantly higher in the samples from patients with PVD compared with those without PVD. Simvastatin inhibited TGF-beta2-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-beta2. 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.

Show MeSH
Related in: MedlinePlus