Potent inhibition of cicatricial contraction in proliferative vitreoretinal diseases by statins

Shuhei Kawahara, Yasuaki Hata, Takeshi Kita, Ryoichi Arita, Muneki Miura, Shintaro Nakao, Yasutaka Mochizuki, Hiroshi Enaida, Tadahisa Kagimoto, Yoshinobu Goto, Ali Hafezi-Moghadam, Tatsuro Ishibashi

Research output: Contribution to journalArticle

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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 vitreo-retinopathy (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-β2 (TGF-β2) were measured by enzyme-linked immunosorbent assay. TGF-β2- 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 simva-statin on cicatrical contraction were assessed both in vitro and in vivo. RESULTS-Human vitreous concentrations of TGF-β2 were significantly higher in the samples from patients with PVD compared with those without PVD. Simvastatin inhibited TGF-β2- 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-β2. 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.

Original languageEnglish
Pages (from-to)2784-2793
Number of pages10
JournalDiabetes
Volume57
Issue number10
DOIs
Publication statusPublished - Oct 1 2008

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Transforming Growth Factors
Simvastatin
Myosin Light Chains
Gels
Phosphorylation
Vitreoretinal Surgery
rho-Associated Kinases
Intravitreal Injections
Retinal Detachment
Diabetic Retinopathy
Protein Transport
Inhibition (Psychology)
Disease Progression
Research Design
Collagen
Enzyme-Linked Immunosorbent Assay
Cell Membrane
Membranes
Therapeutics

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Potent inhibition of cicatricial contraction in proliferative vitreoretinal diseases by statins. / Kawahara, Shuhei; Hata, Yasuaki; Kita, Takeshi; Arita, Ryoichi; Miura, Muneki; Nakao, Shintaro; Mochizuki, Yasutaka; Enaida, Hiroshi; Kagimoto, Tadahisa; Goto, Yoshinobu; Hafezi-Moghadam, Ali; Ishibashi, Tatsuro.

In: Diabetes, Vol. 57, No. 10, 01.10.2008, p. 2784-2793.

Research output: Contribution to journalArticle

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 2008, 'Potent inhibition of cicatricial contraction in proliferative vitreoretinal diseases by statins', Diabetes, vol. 57, no. 10, pp. 2784-2793. https://doi.org/10.2337/db08-0302
Kawahara, Shuhei ; Hata, Yasuaki ; Kita, Takeshi ; Arita, Ryoichi ; Miura, Muneki ; Nakao, Shintaro ; Mochizuki, Yasutaka ; Enaida, Hiroshi ; Kagimoto, Tadahisa ; Goto, Yoshinobu ; Hafezi-Moghadam, Ali ; Ishibashi, Tatsuro. / Potent inhibition of cicatricial contraction in proliferative vitreoretinal diseases by statins. In: Diabetes. 2008 ; Vol. 57, No. 10. pp. 2784-2793.
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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 vitreo-retinopathy (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-β2 (TGF-β2) were measured by enzyme-linked immunosorbent assay. TGF-β2- 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 simva-statin on cicatrical contraction were assessed both in vitro and in vivo. RESULTS-Human vitreous concentrations of TGF-β2 were significantly higher in the samples from patients with PVD compared with those without PVD. Simvastatin inhibited TGF-β2- 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-β2. 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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T1 - Potent inhibition of cicatricial contraction in proliferative vitreoretinal diseases by statins

AU - Kawahara, Shuhei

AU - Hata, Yasuaki

AU - Kita, Takeshi

AU - Arita, Ryoichi

AU - Miura, Muneki

AU - Nakao, Shintaro

AU - Mochizuki, Yasutaka

AU - Enaida, Hiroshi

AU - Kagimoto, Tadahisa

AU - Goto, Yoshinobu

AU - Hafezi-Moghadam, Ali

AU - Ishibashi, Tatsuro

PY - 2008/10/1

Y1 - 2008/10/1

N2 - 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 vitreo-retinopathy (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-β2 (TGF-β2) were measured by enzyme-linked immunosorbent assay. TGF-β2- 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 simva-statin on cicatrical contraction were assessed both in vitro and in vivo. RESULTS-Human vitreous concentrations of TGF-β2 were significantly higher in the samples from patients with PVD compared with those without PVD. Simvastatin inhibited TGF-β2- 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-β2. 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.

AB - 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 vitreo-retinopathy (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-β2 (TGF-β2) were measured by enzyme-linked immunosorbent assay. TGF-β2- 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 simva-statin on cicatrical contraction were assessed both in vitro and in vivo. RESULTS-Human vitreous concentrations of TGF-β2 were significantly higher in the samples from patients with PVD compared with those without PVD. Simvastatin inhibited TGF-β2- 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-β2. 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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