Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage

被引：181

作者：

Arita, Ryoichi ^{[1
]}

Hata, Yasuaki ^{[1
]}

Nakao, Shintaro ^{[1
,2
]}

Kita, Takeshi ^{[1
]}

Miura, Muneki ^{[1
]}

Kawahara, Shuhei ^{[1
]}

Zandi, Souska ^{[2
]}

Almulki, Lama ^{[2
]}

Tayyari, Faryan ^{[2
]}

Shimokawa, Hiroaki ^{[3
]}

Hafezi-Moghadam, Ali ^{[2
]}

Ishibashi, Tatsuro ^{[1
]}

机构：

[1] Kyushu Univ, Grad Sch Med Sci, Dept Ophthalmol, Fukuoka, Japan

[2] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA

[3] Tohoku Univ, Grad Sch Med, Dept Cardiol, Sendai, Miyagi 980, Japan

来源：

DIABETES | 2009年 / 58卷 / 01期

基金：

美国国家卫生研究院;

关键词：

NITRIC-OXIDE SYNTHASE; INTERCELLULAR-ADHESION MOLECULE-1; ENDOTHELIAL DYSFUNCTION; HIGH GLUCOSE; ACTIVATION; EXPRESSION; CELLS; LEUKOSTASIS; GRANULOCYTES; RETINOPATHY;

D O I：

10.2337/db08-0762

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

OBJECTIVE-Leukocyte adhesion in retinal microvasuculature substantially contributes to diabetic retinopathy. Involvement of the Rho/Rho kinase (ROCK) pathway in diabetic microvasculopathy 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 phosphatase 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-positive 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 phosphorylation, 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 apoptosis, 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 N omega-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 retinopathy, especially in its early stages. Diabetes 58:215-227, 2009

引用

页码：215 / 226

页数：12

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