Rho kinase inhibition by fasudil ameliorates diabetes-induced microvascular damage.
Rho kinase inhibition by fasudil ameliorates diabetes-induced microvascular damage.
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DOI：
10.2337/db08-0762
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发表时间：
2009-01
期刊：
影响因子：
7.7
通讯作者：
Ishibashi T
中科院分区：
文献类型：
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作者：
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
视网膜微血管中的白细胞粘附是糖尿病视网膜病变的重要原因。Rho/Rho激酶（ROCK）通路参与糖尿病微血管病变和法舒地尔，选择性ROCK抑制剂的治疗潜力，进行了调查。研究设计和方法-在大鼠视网膜组织中检测RhoA/ROCK和Rho活性的定位。研究了玻璃体内法舒地尔给药对大鼠眼视网膜内皮一氧化氮合酶（eNOS）和肌球蛋白磷酸酶靶蛋白（MYPT）-1磷酸化、细胞间粘附分子-1（ICAM-1）表达、白细胞粘附和内皮损伤的影响。对糖尿病视网膜病变患者或非糖尿病对照组的中性粒细胞与培养的微血管内皮细胞的粘附进行定量。通过测量粘附中性粒细胞和末端转移酶介导的dUTP缺口末端标记阳性内皮细胞的数量，研究法舒地尔对内皮保护的潜力。ROCK-RhoA和ROCK主要共定位于视网膜微血管。在糖尿病大鼠视网膜中观察到显著的Rho激活。玻璃体内法舒地尔显著增加eNOS磷酸化，而减少MYPT-1磷酸化、ICAM-1表达、白细胞粘附和糖尿病大鼠视网膜中受损内皮细胞的数量。糖尿病视网膜病变患者的中性粒细胞对培养的内皮细胞的粘附性显著升高，并引起内皮细胞凋亡，法舒地尔可显著降低内皮细胞凋亡。阻断Fas-FasL相互作用可防止内皮细胞凋亡。法舒地尔对内皮细胞凋亡的保护作用可被NOS抑制剂Nω-硝基-L-精氨酸甲酯显著逆转，而中性粒细胞粘附不受影响。结论：Rho/ROCK通路在糖尿病视网膜微血管病变中起关键作用。法舒地尔通过抑制中性粒细胞粘附和减少嗜中性粒细胞诱导的内皮损伤来保护血管内皮。ROCK抑制可能成为糖尿病视网膜病变治疗的新策略，特别是在其早期阶段。
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 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 retinopathy, especially in its early stages.
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影响因子：
--
作者：
Nakamura RE;Hunter DD;Yi H;Brunken WJ;Hackam AS
通讯作者：
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DOI：
10.1083/jcb.200112126
发表时间：
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期刊：
The Journal of cell biology
影响因子：
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5
作者：
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影响因子：
32.4
作者：
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Laudanna, C
DOI：
10.1083/jcb.138.4.927
发表时间：
1997-08-25
期刊：
The Journal of cell biology
影响因子：
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作者：
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通讯作者：
Hall A