Rho kinase inhibition by fasudil ameliorates diabetes-induced microvascular damage

Ryoichi Arita, Yasuaki Hata, Shintaro Nakao, Takeshi Kita, Muneki Miura, Shuhei Kawahara, Souska Zandi, Lama Almulki, Faryan Tayyari, Hiroaki Shimokawa, Ali Hafezi-Moghadam, Tatsuro Ishibashi

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Abstract

OBJECTIVE-Leukocyte adhesion in retinal microvasuculature substantially contributes to diabetic retinopathy. Involvement of the Rho/Rho kinase (ROCK) pathway in diabetic microvascu- lopathy and therapeutic potential of fasudil, a selective ROCK inhibitor, are investigated. RESEARCH DESIGN AND METHODS-Localization of RhoA/ROCK and Rho activity were examined in retinal tissues of rats. Impact of intravitreal fasudil administration on retinal endothelial nitric oxide synthase (eNOS) and myosin phospha- tase target protein (MYPT)-1 phosphorylation, intercellular adhesion molecule-1 (ICAM-1) expression, leukocyte adhesion, and endothelial damage in rat eyes were investigated. Adhesion of neutrophils from diabetic retinopathy patients or nondiabetic control subjects to cultured microvascular endothelial cells was quantified. The potential of fasudil for endothelial protection was investigated by measuring the number of adherent neutrophils and terminal transferase-mediated dUTP nick-end labeling-posi- tive endothelial cells. RESULTS-RhoA and ROCK colocalized predominantly in retinal microvessels. Significant Rho activation was observed in retinas of diabetic rats. Intravitreal fasudil significantly increased eNOS phosphorylation, whereas it reduced MYPT-1 phosphory- lation, ICAM-1 expression, leukocyte adhesion, and the number of damaged endothelium in retinas of diabetic rats. Neutrophils from diabetic retinopathy patients showed significantly higher adhesion to cultured endothelium and caused endothelial apo- ptosis, which was significantly reduced by fasudil. Blockade of the Fas-FasL interaction prevented endothelial apoptosis. The protective effect of fasudil on endothelial apoptosis was significantly reversed by Nω-nitro-L-arginine methyl ester, a NOS inhibitor, whereas neutrophil adhesion remained unaffected. CONCLUSIONS-The Rho/ROCK pathway plays a critical role in diabetic retinal microvasculopathy. Fasudil protects the vascular endothelium by inhibiting neutrophil adhesion and reducing neutrophil-induced endothelial injury. ROCK inhibition may become a new strategy in the management of diabetic retinopa- thy, especially in its early stages.

Original languageEnglish
Pages (from-to)215-226
Number of pages12
JournalDiabetes
Volume58
Issue number1
DOIs
Publication statusPublished - Jan 1 2009

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rho-Associated Kinases
Neutrophils
Diabetic Retinopathy
Nitric Oxide Synthase Type III
Phosphorylation
Intercellular Adhesion Molecule-1
Myosins
Endothelium
Retina
Leukocytes
Endothelial Cells
Apoptosis
Vascular Endothelium
Transferases
Microvessels
fasudil
Leukocyte Count
Proteins
Research Design
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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Rho kinase inhibition by fasudil ameliorates diabetes-induced microvascular damage. / Arita, Ryoichi; Hata, Yasuaki; Nakao, Shintaro; Kita, Takeshi; Miura, Muneki; Kawahara, Shuhei; Zandi, Souska; Almulki, Lama; Tayyari, Faryan; Shimokawa, Hiroaki; Hafezi-Moghadam, Ali; Ishibashi, Tatsuro.

In: Diabetes, Vol. 58, No. 1, 01.01.2009, p. 215-226.

Research output: Contribution to journalArticle

Arita, R, Hata, Y, Nakao, S, Kita, T, Miura, M, Kawahara, S, Zandi, S, Almulki, L, Tayyari, F, Shimokawa, H, Hafezi-Moghadam, A & Ishibashi, T 2009, 'Rho kinase inhibition by fasudil ameliorates diabetes-induced microvascular damage', Diabetes, vol. 58, no. 1, pp. 215-226. https://doi.org/10.2337/db08-0762
Arita, Ryoichi ; Hata, Yasuaki ; Nakao, Shintaro ; Kita, Takeshi ; Miura, Muneki ; Kawahara, Shuhei ; Zandi, Souska ; Almulki, Lama ; Tayyari, Faryan ; Shimokawa, Hiroaki ; Hafezi-Moghadam, Ali ; Ishibashi, Tatsuro. / Rho kinase inhibition by fasudil ameliorates diabetes-induced microvascular damage. In: Diabetes. 2009 ; Vol. 58, No. 1. pp. 215-226.
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abstract = "OBJECTIVE-Leukocyte adhesion in retinal microvasuculature substantially contributes to diabetic retinopathy. Involvement of the Rho/Rho kinase (ROCK) pathway in diabetic microvascu- lopathy and therapeutic potential of fasudil, a selective ROCK inhibitor, are investigated. RESEARCH DESIGN AND METHODS-Localization of RhoA/ROCK and Rho activity were examined in retinal tissues of rats. Impact of intravitreal fasudil administration on retinal endothelial nitric oxide synthase (eNOS) and myosin phospha- tase target protein (MYPT)-1 phosphorylation, intercellular adhesion molecule-1 (ICAM-1) expression, leukocyte adhesion, and endothelial damage in rat eyes were investigated. Adhesion of neutrophils from diabetic retinopathy patients or nondiabetic control subjects to cultured microvascular endothelial cells was quantified. The potential of fasudil for endothelial protection was investigated by measuring the number of adherent neutrophils and terminal transferase-mediated dUTP nick-end labeling-posi- tive endothelial cells. RESULTS-RhoA and ROCK colocalized predominantly in retinal microvessels. Significant Rho activation was observed in retinas of diabetic rats. Intravitreal fasudil significantly increased eNOS phosphorylation, whereas it reduced MYPT-1 phosphory- lation, ICAM-1 expression, leukocyte adhesion, and the number of damaged endothelium in retinas of diabetic rats. Neutrophils from diabetic retinopathy patients showed significantly higher adhesion to cultured endothelium and caused endothelial apo- ptosis, which was significantly reduced by fasudil. Blockade of the Fas-FasL interaction prevented endothelial apoptosis. The protective effect of fasudil on endothelial apoptosis was significantly reversed by Nω-nitro-L-arginine methyl ester, a NOS inhibitor, whereas neutrophil adhesion remained unaffected. CONCLUSIONS-The Rho/ROCK pathway plays a critical role in diabetic retinal microvasculopathy. Fasudil protects the vascular endothelium by inhibiting neutrophil adhesion and reducing neutrophil-induced endothelial injury. ROCK inhibition may become a new strategy in the management of diabetic retinopa- thy, especially in its early stages.",
author = "Ryoichi Arita and Yasuaki Hata and Shintaro Nakao and Takeshi Kita and Muneki Miura and Shuhei Kawahara and Souska Zandi and Lama Almulki and Faryan Tayyari and Hiroaki Shimokawa and Ali Hafezi-Moghadam and Tatsuro Ishibashi",
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AU - Arita, Ryoichi

AU - Hata, Yasuaki

AU - Nakao, Shintaro

AU - Kita, Takeshi

AU - Miura, Muneki

AU - Kawahara, Shuhei

AU - Zandi, Souska

AU - Almulki, Lama

AU - Tayyari, Faryan

AU - Shimokawa, Hiroaki

AU - Hafezi-Moghadam, Ali

AU - Ishibashi, Tatsuro

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N2 - OBJECTIVE-Leukocyte adhesion in retinal microvasuculature substantially contributes to diabetic retinopathy. Involvement of the Rho/Rho kinase (ROCK) pathway in diabetic microvascu- lopathy and therapeutic potential of fasudil, a selective ROCK inhibitor, are investigated. RESEARCH DESIGN AND METHODS-Localization of RhoA/ROCK and Rho activity were examined in retinal tissues of rats. Impact of intravitreal fasudil administration on retinal endothelial nitric oxide synthase (eNOS) and myosin phospha- tase target protein (MYPT)-1 phosphorylation, intercellular adhesion molecule-1 (ICAM-1) expression, leukocyte adhesion, and endothelial damage in rat eyes were investigated. Adhesion of neutrophils from diabetic retinopathy patients or nondiabetic control subjects to cultured microvascular endothelial cells was quantified. The potential of fasudil for endothelial protection was investigated by measuring the number of adherent neutrophils and terminal transferase-mediated dUTP nick-end labeling-posi- tive endothelial cells. RESULTS-RhoA and ROCK colocalized predominantly in retinal microvessels. Significant Rho activation was observed in retinas of diabetic rats. Intravitreal fasudil significantly increased eNOS phosphorylation, whereas it reduced MYPT-1 phosphory- lation, ICAM-1 expression, leukocyte adhesion, and the number of damaged endothelium in retinas of diabetic rats. Neutrophils from diabetic retinopathy patients showed significantly higher adhesion to cultured endothelium and caused endothelial apo- ptosis, which was significantly reduced by fasudil. Blockade of the Fas-FasL interaction prevented endothelial apoptosis. The protective effect of fasudil on endothelial apoptosis was significantly reversed by Nω-nitro-L-arginine methyl ester, a NOS inhibitor, whereas neutrophil adhesion remained unaffected. CONCLUSIONS-The Rho/ROCK pathway plays a critical role in diabetic retinal microvasculopathy. Fasudil protects the vascular endothelium by inhibiting neutrophil adhesion and reducing neutrophil-induced endothelial injury. ROCK inhibition may become a new strategy in the management of diabetic retinopa- thy, especially in its early stages.

AB - OBJECTIVE-Leukocyte adhesion in retinal microvasuculature substantially contributes to diabetic retinopathy. Involvement of the Rho/Rho kinase (ROCK) pathway in diabetic microvascu- lopathy and therapeutic potential of fasudil, a selective ROCK inhibitor, are investigated. RESEARCH DESIGN AND METHODS-Localization of RhoA/ROCK and Rho activity were examined in retinal tissues of rats. Impact of intravitreal fasudil administration on retinal endothelial nitric oxide synthase (eNOS) and myosin phospha- tase target protein (MYPT)-1 phosphorylation, intercellular adhesion molecule-1 (ICAM-1) expression, leukocyte adhesion, and endothelial damage in rat eyes were investigated. Adhesion of neutrophils from diabetic retinopathy patients or nondiabetic control subjects to cultured microvascular endothelial cells was quantified. The potential of fasudil for endothelial protection was investigated by measuring the number of adherent neutrophils and terminal transferase-mediated dUTP nick-end labeling-posi- tive endothelial cells. RESULTS-RhoA and ROCK colocalized predominantly in retinal microvessels. Significant Rho activation was observed in retinas of diabetic rats. Intravitreal fasudil significantly increased eNOS phosphorylation, whereas it reduced MYPT-1 phosphory- lation, ICAM-1 expression, leukocyte adhesion, and the number of damaged endothelium in retinas of diabetic rats. Neutrophils from diabetic retinopathy patients showed significantly higher adhesion to cultured endothelium and caused endothelial apo- ptosis, which was significantly reduced by fasudil. Blockade of the Fas-FasL interaction prevented endothelial apoptosis. The protective effect of fasudil on endothelial apoptosis was significantly reversed by Nω-nitro-L-arginine methyl ester, a NOS inhibitor, whereas neutrophil adhesion remained unaffected. CONCLUSIONS-The Rho/ROCK pathway plays a critical role in diabetic retinal microvasculopathy. Fasudil protects the vascular endothelium by inhibiting neutrophil adhesion and reducing neutrophil-induced endothelial injury. ROCK inhibition may become a new strategy in the management of diabetic retinopa- thy, especially in its early stages.

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