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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

TGF-β2 expression in the vitreous. A: Vitreous samples were collected from patients with non-PVD (macular hole) and PVD (PDR and PVR). Concentrations of TGF-β2 in the vitreous were measured by enzyme-linked immunosorbent assay (macular hole, n = 27; PDR, n = 53; PVR, n = 22). **P < 0.01 compared with macular hole. B: Hyalocytes were embedded in type I collagen gels (n = 4). After starvation and pretreatment with 1 μg/ml anti–TGF-β2 antibody or 1 μg/ml IgG for 1 h, the collagen gels were treated with vitreous samples from patients with PVD. Five days after the treatment, the gels were photographed. C: 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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f1: TGF-β2 expression in the vitreous. A: Vitreous samples were collected from patients with non-PVD (macular hole) and PVD (PDR and PVR). Concentrations of TGF-β2 in the vitreous were measured by enzyme-linked immunosorbent assay (macular hole, n = 27; PDR, n = 53; PVR, n = 22). **P < 0.01 compared with macular hole. B: Hyalocytes were embedded in type I collagen gels (n = 4). After starvation and pretreatment with 1 μg/ml anti–TGF-β2 antibody or 1 μg/ml IgG for 1 h, the collagen gels were treated with vitreous samples from patients with PVD. Five days after the treatment, the gels were photographed. C: The diameter of the collagen gels was measured and expressed as percentage of the average diameter of the control group. *P < 0.05.

Mentions: The median TGF-β2 protein concentrations, 2.35 ng/ml (range 0.72–5.26) in macular hole (n = 27), 4.74 ng/ml (1.60–13.0) in PDR (n = 53), and 4.48 ng/ml (2.52–21.6) in PVR (n = 22) patients, were significantly higher in PDR or PVR patients than in patients with macular hole (P < 0.01) (Fig. 1A). The median TGF-β2 protein concentration in the vitreous samples from patients with PDR or PVR showed no significant difference (P = 0.6).


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)

TGF-β2 expression in the vitreous. A: Vitreous samples were collected from patients with non-PVD (macular hole) and PVD (PDR and PVR). Concentrations of TGF-β2 in the vitreous were measured by enzyme-linked immunosorbent assay (macular hole, n = 27; PDR, n = 53; PVR, n = 22). **P < 0.01 compared with macular hole. B: Hyalocytes were embedded in type I collagen gels (n = 4). After starvation and pretreatment with 1 μg/ml anti–TGF-β2 antibody or 1 μg/ml IgG for 1 h, the collagen gels were treated with vitreous samples from patients with PVD. Five days after the treatment, the gels were photographed. C: 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

f1: TGF-β2 expression in the vitreous. A: Vitreous samples were collected from patients with non-PVD (macular hole) and PVD (PDR and PVR). Concentrations of TGF-β2 in the vitreous were measured by enzyme-linked immunosorbent assay (macular hole, n = 27; PDR, n = 53; PVR, n = 22). **P < 0.01 compared with macular hole. B: Hyalocytes were embedded in type I collagen gels (n = 4). After starvation and pretreatment with 1 μg/ml anti–TGF-β2 antibody or 1 μg/ml IgG for 1 h, the collagen gels were treated with vitreous samples from patients with PVD. Five days after the treatment, the gels were photographed. C: The diameter of the collagen gels was measured and expressed as percentage of the average diameter of the control group. *P < 0.05.
Mentions: The median TGF-β2 protein concentrations, 2.35 ng/ml (range 0.72–5.26) in macular hole (n = 27), 4.74 ng/ml (1.60–13.0) in PDR (n = 53), and 4.48 ng/ml (2.52–21.6) in PVR (n = 22) patients, were significantly higher in PDR or PVR patients than in patients with macular hole (P < 0.01) (Fig. 1A). The median TGF-β2 protein concentration in the vitreous samples from patients with PDR or PVR showed no significant difference (P = 0.6).

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