Limits...
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.

Show MeSH

Related in: MedlinePlus

Inhibitory effect of simvastatin on the Rho translocation to the plasma membrane. A: Hyalocytes were pretreated with 5 μmol/l simvastatin with or without mevalonate (Mev) and then treated with 3 ng/ml TGF-β2 for 24 h. Plasma membrane proteins were isolated and subjected to Western blot analysis with an antibody against Rho. B: Signal intensities were expressed as percentage of control intensity. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2551690&req=5

f4: Inhibitory effect of simvastatin on the Rho translocation to the plasma membrane. A: Hyalocytes were pretreated with 5 μmol/l simvastatin with or without mevalonate (Mev) and then treated with 3 ng/ml TGF-β2 for 24 h. Plasma membrane proteins were isolated and subjected to Western blot analysis with an antibody against Rho. B: Signal intensities were expressed as percentage of control intensity. *P < 0.05.

Mentions: TGF-β2 significantly enhanced the Rho translocation to the plasma membrane (P < 0.05), whereas simvastatin suppressed the translocation (Fig. 4A and B). However, the effect of simvastatin was reversed in the presence of 400 μmol/l mevalonate, a component of the mevalonate pathway. These findings suggest that simvastatin inhibits Rho/Rho kinase pathway by preventing Rho from translocating to the plasma membrane via inhibition of the mevalonate pathway.


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 effect of simvastatin on the Rho translocation to the plasma membrane. A: Hyalocytes were pretreated with 5 μmol/l simvastatin with or without mevalonate (Mev) and then treated with 3 ng/ml TGF-β2 for 24 h. Plasma membrane proteins were isolated and subjected to Western blot analysis with an antibody against Rho. B: Signal intensities were expressed as percentage of control intensity. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Inhibitory effect of simvastatin on the Rho translocation to the plasma membrane. A: Hyalocytes were pretreated with 5 μmol/l simvastatin with or without mevalonate (Mev) and then treated with 3 ng/ml TGF-β2 for 24 h. Plasma membrane proteins were isolated and subjected to Western blot analysis with an antibody against Rho. B: Signal intensities were expressed as percentage of control intensity. *P < 0.05.
Mentions: TGF-β2 significantly enhanced the Rho translocation to the plasma membrane (P < 0.05), whereas simvastatin suppressed the translocation (Fig. 4A and B). However, the effect of simvastatin was reversed in the presence of 400 μmol/l mevalonate, a component of the mevalonate pathway. These findings suggest that simvastatin inhibits Rho/Rho kinase pathway by preventing Rho from translocating to the plasma membrane via inhibition of the mevalonate pathway.

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