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Fasudil ameliorates endothelial dysfunction in streptozotocin-induced diabetic rats: a possible role of Rho kinase

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Abstract

Endothelial dysfunction is a major contributor to the pathogenesis of vascular disease in diabetes mellitus and RhoA/Rho-kinase (ROCK) system appears to play a crucial role in this setting. The present study was conducted to investigate the effect of the selective ROCK inhibitor, fasudil, on diabetes-related endothelial dysfunction and elucidated its underlying mechanism(s). Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg), and fasudil (5 mg/kg per day) was orally administered for 8 weeks. Our results showed that fasudil administration attenuated the increased activity/expression of ROCK (627.5 ± 27 vs. 247.8 ± 19.1) and the NADPH oxidase subunits, NOX2 and p47phox, in diabetic rat aorta. Fasudil could reduce the elevated tumor necrosis factor (TNF)-α (70.2 ± 14.1 vs. 25.3 ± 5.2) and transforming growth factor (TGF-β) levels and restored the deficit in antioxidant level of the diabetic aorta. Additionally, fasudil markedly improved the endothelial dysfunction in the diabetic aorta (73.8 ± 8.1 vs. 47.42 ± 8.69) and corrected the dysregulated endothelial nitric oxide (eNOS) expression. In conclusion, the present study demonstrates that fasudil effectively ameliorates the endothelial dysfunction in STZ-induced diabetic rats through inhibition of the Rho/ROCK pathway and thereby reducing the TNF-α-mediated NADPH oxidase activation.

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Acknowledgements

We are grateful to grateful to Prof. Adel Bakeer, Department of Pathology, Faculty of Veterinary Medicine, Cairo University, for his kind help in performing histopathological studies and interpretation of the results.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt

    Amal Hofni & Basim A. Shehata Messiha

  2. Department of Pharmacology, Faculty of Medicine, Assuit University, Assuit, Egypt

    Safwat A. Mangoura

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  1. Amal Hofni
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  2. Basim A. Shehata Messiha
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Correspondence to Amal Hofni.

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Hofni, A., Shehata Messiha, B.A. & Mangoura, S.A. Fasudil ameliorates endothelial dysfunction in streptozotocin-induced diabetic rats: a possible role of Rho kinase. Naunyn-Schmiedeberg's Arch Pharmacol 390, 801–811 (2017). https://doi.org/10.1007/s00210-017-1379-y

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