Role of TGF-β in proliferative vitreoretinal diseases and ROCK as a therapeutic target

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

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Abstract

Cicatricial contraction of preretinal fibrous membrane is a cause of severe vision loss in proliferative vitreoretinal diseases such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). TGF-β is overexpressed in the vitreous of patients with proliferative vitreoretinal diseases and is also detectable in the contractile membranes. Therefore, TGF-β is presumed to contribute to the cicatricial contraction of the membranes, however, the underlying mechanisms and TGF-β's importance among various other factors remain to be elucidated. Vitreous samples from PDR or PVR patients caused significantly larger contraction of hyalocyte-containing collagen gels, compared with nonproliferative controls. The contractile effect was strongly correlated with the vitreal concentration of activated TGF-β2 (r = 0.82, P < 0.0001). PDR or PVR vitreous promoted expression of α-smooth muscle actin (α-SMA) and phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase (ROCK), both of which were dramatically but incompletely suppressed by TGF-β blockade. In contrast, fasudil, a potent and selective ROCK inhibitor, almost completely blocked the vitreous-induced MLC phosphorylation and collagen gel contraction. Fasudil disrupted α-SMA organization, but it did not affect its vitreal expression. In vivo, fasudil significantly inhibited the progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells by electroretinographic and histological analyses. These results elucidate the critical role of TGF-β in mediating cicatricial contraction in proliferative vitreoretinal diseases. ROCK, a key downstream mediator of TGF-β and other factors might become a unique therapeutic target in the treatment of proliferative vitreoretinal diseases.

Original languageEnglish
Pages (from-to)17504-17509
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number45
DOIs
Publication statusPublished - Nov 11 2008

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Proliferative Vitreoretinopathy
Diabetic Retinopathy
Myosin Light Chains
Membranes
Collagen
Gels
Phosphorylation
rho-Associated Kinases
Therapeutics
Smooth Muscle
Actins
Cell Survival
Rabbits
fasudil

All Science Journal Classification (ASJC) codes

  • General

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Role of TGF-β in proliferative vitreoretinal diseases and ROCK as a therapeutic target. / Kita, Takeshi; Hata, Yasuaki; Arita, Ryoichi; Kawahara, Shuhei; Miura, Muneki; Nakao, Shintaro; Mochizuki, Yasutaka; Enaida, Hiroshi; Goto, Yoshinobu; Shimokawa, Hiroaki; Hafezi-Moghadam, Ali; Ishibashi, Tatsuro.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 45, 11.11.2008, p. 17504-17509.

Research output: Contribution to journalArticle

Kita, T, Hata, Y, Arita, R, Kawahara, S, Miura, M, Nakao, S, Mochizuki, Y, Enaida, H, Goto, Y, Shimokawa, H, Hafezi-Moghadam, A & Ishibashi, T 2008, 'Role of TGF-β in proliferative vitreoretinal diseases and ROCK as a therapeutic target', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 45, pp. 17504-17509. https://doi.org/10.1073/pnas.0804054105
Kita, Takeshi ; Hata, Yasuaki ; Arita, Ryoichi ; Kawahara, Shuhei ; Miura, Muneki ; Nakao, Shintaro ; Mochizuki, Yasutaka ; Enaida, Hiroshi ; Goto, Yoshinobu ; Shimokawa, Hiroaki ; Hafezi-Moghadam, Ali ; Ishibashi, Tatsuro. / Role of TGF-β in proliferative vitreoretinal diseases and ROCK as a therapeutic target. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 45. pp. 17504-17509.
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abstract = "Cicatricial contraction of preretinal fibrous membrane is a cause of severe vision loss in proliferative vitreoretinal diseases such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). TGF-β is overexpressed in the vitreous of patients with proliferative vitreoretinal diseases and is also detectable in the contractile membranes. Therefore, TGF-β is presumed to contribute to the cicatricial contraction of the membranes, however, the underlying mechanisms and TGF-β's importance among various other factors remain to be elucidated. Vitreous samples from PDR or PVR patients caused significantly larger contraction of hyalocyte-containing collagen gels, compared with nonproliferative controls. The contractile effect was strongly correlated with the vitreal concentration of activated TGF-β2 (r = 0.82, P < 0.0001). PDR or PVR vitreous promoted expression of α-smooth muscle actin (α-SMA) and phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase (ROCK), both of which were dramatically but incompletely suppressed by TGF-β blockade. In contrast, fasudil, a potent and selective ROCK inhibitor, almost completely blocked the vitreous-induced MLC phosphorylation and collagen gel contraction. Fasudil disrupted α-SMA organization, but it did not affect its vitreal expression. In vivo, fasudil significantly inhibited the progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells by electroretinographic and histological analyses. These results elucidate the critical role of TGF-β in mediating cicatricial contraction in proliferative vitreoretinal diseases. ROCK, a key downstream mediator of TGF-β and other factors might become a unique therapeutic target in the treatment of proliferative vitreoretinal diseases.",
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AU - Miura, Muneki

AU - Nakao, Shintaro

AU - Mochizuki, Yasutaka

AU - Enaida, Hiroshi

AU - Goto, Yoshinobu

AU - Shimokawa, Hiroaki

AU - Hafezi-Moghadam, Ali

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N2 - Cicatricial contraction of preretinal fibrous membrane is a cause of severe vision loss in proliferative vitreoretinal diseases such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). TGF-β is overexpressed in the vitreous of patients with proliferative vitreoretinal diseases and is also detectable in the contractile membranes. Therefore, TGF-β is presumed to contribute to the cicatricial contraction of the membranes, however, the underlying mechanisms and TGF-β's importance among various other factors remain to be elucidated. Vitreous samples from PDR or PVR patients caused significantly larger contraction of hyalocyte-containing collagen gels, compared with nonproliferative controls. The contractile effect was strongly correlated with the vitreal concentration of activated TGF-β2 (r = 0.82, P < 0.0001). PDR or PVR vitreous promoted expression of α-smooth muscle actin (α-SMA) and phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase (ROCK), both of which were dramatically but incompletely suppressed by TGF-β blockade. In contrast, fasudil, a potent and selective ROCK inhibitor, almost completely blocked the vitreous-induced MLC phosphorylation and collagen gel contraction. Fasudil disrupted α-SMA organization, but it did not affect its vitreal expression. In vivo, fasudil significantly inhibited the progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells by electroretinographic and histological analyses. These results elucidate the critical role of TGF-β in mediating cicatricial contraction in proliferative vitreoretinal diseases. ROCK, a key downstream mediator of TGF-β and other factors might become a unique therapeutic target in the treatment of proliferative vitreoretinal diseases.

AB - Cicatricial contraction of preretinal fibrous membrane is a cause of severe vision loss in proliferative vitreoretinal diseases such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). TGF-β is overexpressed in the vitreous of patients with proliferative vitreoretinal diseases and is also detectable in the contractile membranes. Therefore, TGF-β is presumed to contribute to the cicatricial contraction of the membranes, however, the underlying mechanisms and TGF-β's importance among various other factors remain to be elucidated. Vitreous samples from PDR or PVR patients caused significantly larger contraction of hyalocyte-containing collagen gels, compared with nonproliferative controls. The contractile effect was strongly correlated with the vitreal concentration of activated TGF-β2 (r = 0.82, P < 0.0001). PDR or PVR vitreous promoted expression of α-smooth muscle actin (α-SMA) and phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase (ROCK), both of which were dramatically but incompletely suppressed by TGF-β blockade. In contrast, fasudil, a potent and selective ROCK inhibitor, almost completely blocked the vitreous-induced MLC phosphorylation and collagen gel contraction. Fasudil disrupted α-SMA organization, but it did not affect its vitreal expression. In vivo, fasudil significantly inhibited the progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells by electroretinographic and histological analyses. These results elucidate the critical role of TGF-β in mediating cicatricial contraction in proliferative vitreoretinal diseases. ROCK, a key downstream mediator of TGF-β and other factors might become a unique therapeutic target in the treatment of proliferative vitreoretinal diseases.

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