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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 experimental PVR in rabbit eyes. Rabbits underwent vitrectomy and intravitreal injection of fibroblasts with and without simvastatin on day 0. The eyes were injected with same contents of simvastatin on days 1, 3, 5, and 7 and examined using indirect ophthalmoscope as long as 28 days after the surgery. A: A representative vehicle-injected eye with PVR in stage 5, 28 days after the surgery. Proliferative membranes were observed in the vitreous cavity, causing a traction to the retina and retinal detachment. B: A representative simvastatin-injected eye (15 μmol/l) with PVR in stage 1. A thin proliferative membrane was observed, however, there was no evidence of tractional retinal detachment. C: Clinical observations were categorized according to the PVR classification of Fastenberg et al. (35). Stage 1, intravitreal membrane; stage 2, focal traction, localized vascular changes, hyperemia, engorgement, dilation, and blood vessel elevation; stage 3, localized detachment of medullary ray; stage 4, extensive retinal detachment, total medullary ray detachment, and peripapillary retinal detachment; and stage 5, total retinal detachment. •, vehicle; □, 5 μmol/l simvastatin; ▴, 15 μmol/l simvastatin. **P < 0.01, *P < 0.05; NS, not significant compared with vehicle.
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f7: Inhibitory effects of simvastatin on experimental PVR in rabbit eyes. Rabbits underwent vitrectomy and intravitreal injection of fibroblasts with and without simvastatin on day 0. The eyes were injected with same contents of simvastatin on days 1, 3, 5, and 7 and examined using indirect ophthalmoscope as long as 28 days after the surgery. A: A representative vehicle-injected eye with PVR in stage 5, 28 days after the surgery. Proliferative membranes were observed in the vitreous cavity, causing a traction to the retina and retinal detachment. B: A representative simvastatin-injected eye (15 μmol/l) with PVR in stage 1. A thin proliferative membrane was observed, however, there was no evidence of tractional retinal detachment. C: Clinical observations were categorized according to the PVR classification of Fastenberg et al. (35). Stage 1, intravitreal membrane; stage 2, focal traction, localized vascular changes, hyperemia, engorgement, dilation, and blood vessel elevation; stage 3, localized detachment of medullary ray; stage 4, extensive retinal detachment, total medullary ray detachment, and peripapillary retinal detachment; and stage 5, total retinal detachment. •, vehicle; □, 5 μmol/l simvastatin; ▴, 15 μmol/l simvastatin. **P < 0.01, *P < 0.05; NS, not significant compared with vehicle.

Mentions: The control eyes of rabbits injected with vehicle developed PVR and were accompanied by proliferative membrane formation and cicatricial contraction, resulting in tractional retinal detachment (Fig. 7A). In comparison, 5 and 15 μmol/l simvastatin (final intravitreal concentrations) significantly prevented PVR development (Fig. 7C). Simvastatin inhibited the contraction of the proliferative membrane, and the membranes in eyes treated with simvastatin were much thinner than those in vehicle-treated eyes (Fig. 7B). After simvastatin injections were stopped at day 7, the eyes treated with 5 μmol/l simvastatin developed a mild but significant PVR, whereas no significant PVR development was observed in the eyes treated with 15 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 experimental PVR in rabbit eyes. Rabbits underwent vitrectomy and intravitreal injection of fibroblasts with and without simvastatin on day 0. The eyes were injected with same contents of simvastatin on days 1, 3, 5, and 7 and examined using indirect ophthalmoscope as long as 28 days after the surgery. A: A representative vehicle-injected eye with PVR in stage 5, 28 days after the surgery. Proliferative membranes were observed in the vitreous cavity, causing a traction to the retina and retinal detachment. B: A representative simvastatin-injected eye (15 μmol/l) with PVR in stage 1. A thin proliferative membrane was observed, however, there was no evidence of tractional retinal detachment. C: Clinical observations were categorized according to the PVR classification of Fastenberg et al. (35). Stage 1, intravitreal membrane; stage 2, focal traction, localized vascular changes, hyperemia, engorgement, dilation, and blood vessel elevation; stage 3, localized detachment of medullary ray; stage 4, extensive retinal detachment, total medullary ray detachment, and peripapillary retinal detachment; and stage 5, total retinal detachment. •, vehicle; □, 5 μmol/l simvastatin; ▴, 15 μmol/l simvastatin. **P < 0.01, *P < 0.05; NS, not significant compared with vehicle.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2551690&req=5

f7: Inhibitory effects of simvastatin on experimental PVR in rabbit eyes. Rabbits underwent vitrectomy and intravitreal injection of fibroblasts with and without simvastatin on day 0. The eyes were injected with same contents of simvastatin on days 1, 3, 5, and 7 and examined using indirect ophthalmoscope as long as 28 days after the surgery. A: A representative vehicle-injected eye with PVR in stage 5, 28 days after the surgery. Proliferative membranes were observed in the vitreous cavity, causing a traction to the retina and retinal detachment. B: A representative simvastatin-injected eye (15 μmol/l) with PVR in stage 1. A thin proliferative membrane was observed, however, there was no evidence of tractional retinal detachment. C: Clinical observations were categorized according to the PVR classification of Fastenberg et al. (35). Stage 1, intravitreal membrane; stage 2, focal traction, localized vascular changes, hyperemia, engorgement, dilation, and blood vessel elevation; stage 3, localized detachment of medullary ray; stage 4, extensive retinal detachment, total medullary ray detachment, and peripapillary retinal detachment; and stage 5, total retinal detachment. •, vehicle; □, 5 μmol/l simvastatin; ▴, 15 μmol/l simvastatin. **P < 0.01, *P < 0.05; NS, not significant compared with vehicle.
Mentions: The control eyes of rabbits injected with vehicle developed PVR and were accompanied by proliferative membrane formation and cicatricial contraction, resulting in tractional retinal detachment (Fig. 7A). In comparison, 5 and 15 μmol/l simvastatin (final intravitreal concentrations) significantly prevented PVR development (Fig. 7C). Simvastatin inhibited the contraction of the proliferative membrane, and the membranes in eyes treated with simvastatin were much thinner than those in vehicle-treated eyes (Fig. 7B). After simvastatin injections were stopped at day 7, the eyes treated with 5 μmol/l simvastatin developed a mild but significant PVR, whereas no significant PVR development was observed in the eyes treated with 15 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