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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

Inhibitory effects of simvastatin on vitreous-induced MLC phosphorylation and contraction of hyalocyte-containing collagen gels. A: Starved hyalocytes were pretreated with 5 μmol/l simvastatin for 30 min and subsequently treated with or without 400 μl vitreous samples of non-PVD (macular hole) or PVD (PDR and PVR) for 24 h. Total cell lysates were subjected to Western blot analysis with an antibody against p-MLC. Lane loading differences were normalized by reblotting the membranes with an antibody against MLC and GAPDH. B: Signal intensity ratios (p-MLC to GAPDH) were expressed as percentage of control intensity ratio. C: Hyalocytes were embedded in type I collagen gels (n = 4). After starvation and pretreatment with 5 μmol/l simvastatin for 24 h, the collagen gels were stimulated with 400 μl vitreous samples of non-PVD or PVD. Five days after the stimulation, the gels were photographed. D: The diameter of the collagen gels was measured and expressed as percentage of the average diameter of the control group. *P < 0.05.
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f6: Inhibitory effects of simvastatin on vitreous-induced MLC phosphorylation and contraction of hyalocyte-containing collagen gels. A: Starved hyalocytes were pretreated with 5 μmol/l simvastatin for 30 min and subsequently treated with or without 400 μl vitreous samples of non-PVD (macular hole) or PVD (PDR and PVR) for 24 h. Total cell lysates were subjected to Western blot analysis with an antibody against p-MLC. Lane loading differences were normalized by reblotting the membranes with an antibody against MLC and GAPDH. B: Signal intensity ratios (p-MLC to GAPDH) were expressed as percentage of control intensity ratio. C: Hyalocytes were embedded in type I collagen gels (n = 4). After starvation and pretreatment with 5 μmol/l simvastatin for 24 h, the collagen gels were stimulated with 400 μl vitreous samples of non-PVD or PVD. Five days after the stimulation, the gels were photographed. D: The diameter of the collagen gels was measured and expressed as percentage of the average diameter of the control group. *P < 0.05.

Mentions: Vitreous samples from patients with PVD caused a significantly larger enhancement of MLC phosphorylation than those from patients with non-PVD (Fig. 6A and B). Simvastatin (5 μmol/l) strongly attenuated the vitreous-induced MLC phosphorylation. Expression of GAPDH did not change after the treatment with simvastatin or stimulation with vitreous samples. However, total MLC increased in cells stimulated with the vitreous samples compared with cells without vitreous treatment, and the increase was larger in cells stimulated with vitreous samples from patients with PVD than those from patients without PVD. These increases in an amount of total MLC were suppressed by 5 μmol/l simvastatin.


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)

Inhibitory effects of simvastatin on vitreous-induced MLC phosphorylation and contraction of hyalocyte-containing collagen gels. A: Starved hyalocytes were pretreated with 5 μmol/l simvastatin for 30 min and subsequently treated with or without 400 μl vitreous samples of non-PVD (macular hole) or PVD (PDR and PVR) for 24 h. Total cell lysates were subjected to Western blot analysis with an antibody against p-MLC. Lane loading differences were normalized by reblotting the membranes with an antibody against MLC and GAPDH. B: Signal intensity ratios (p-MLC to GAPDH) were expressed as percentage of control intensity ratio. C: Hyalocytes were embedded in type I collagen gels (n = 4). After starvation and pretreatment with 5 μmol/l simvastatin for 24 h, the collagen gels were stimulated with 400 μl vitreous samples of non-PVD or PVD. Five days after the stimulation, the gels were photographed. D: The diameter of the collagen gels was measured and expressed as percentage of the average diameter of the control group. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Inhibitory effects of simvastatin on vitreous-induced MLC phosphorylation and contraction of hyalocyte-containing collagen gels. A: Starved hyalocytes were pretreated with 5 μmol/l simvastatin for 30 min and subsequently treated with or without 400 μl vitreous samples of non-PVD (macular hole) or PVD (PDR and PVR) for 24 h. Total cell lysates were subjected to Western blot analysis with an antibody against p-MLC. Lane loading differences were normalized by reblotting the membranes with an antibody against MLC and GAPDH. B: Signal intensity ratios (p-MLC to GAPDH) were expressed as percentage of control intensity ratio. C: Hyalocytes were embedded in type I collagen gels (n = 4). After starvation and pretreatment with 5 μmol/l simvastatin for 24 h, the collagen gels were stimulated with 400 μl vitreous samples of non-PVD or PVD. Five days after the stimulation, the gels were photographed. D: The diameter of the collagen gels was measured and expressed as percentage of the average diameter of the control group. *P < 0.05.
Mentions: Vitreous samples from patients with PVD caused a significantly larger enhancement of MLC phosphorylation than those from patients with non-PVD (Fig. 6A and B). Simvastatin (5 μmol/l) strongly attenuated the vitreous-induced MLC phosphorylation. Expression of GAPDH did not change after the treatment with simvastatin or stimulation with vitreous samples. However, total MLC increased in cells stimulated with the vitreous samples compared with cells without vitreous treatment, and the increase was larger in cells stimulated with vitreous samples from patients with PVD than those from patients without PVD. These increases in an amount of total MLC were suppressed by 5 μmol/l simvastatin.

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