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.
Keywords: Diabetes-oxidative stress; Endothelial dysfunction; Fasudil; RhoA kinase; Streptozotocin.