Long-term administration of fasudil improves cardiomyopathy in streptozotocin-induced diabetic rats

• Published in: Food and chemical toxicology 2012-06, Vol.50 (6), p.1874-1882
• Main Authors: Guan, Sheng-jiang, Ma, Zhi-hong, Wu, Yan-ling, Zhang, Jian-ping, Liang, Feng, Woodrow Weiss, J., Guo, Qian-yu, Wang, Jiang-yan, Ji, En-sheng, Chu, Li
• Format: Article
• Language: English
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - therapeutic use; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; animal models; Animals; antioxidant activity; Antioxidants - metabolism; apoptosis; Apoptosis - drug effects; Biological and medical sciences; Blood Glucose - metabolism; blood serum; Body Weight - drug effects; Body Weight - physiology; Captopril - therapeutic use; Cardiology. Vascular system; cardiomyopathy; collagen; creatine kinase; diabetes; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes. Impaired glucose tolerance; Diabetic Cardiomyopathies - enzymology; Diabetic Cardiomyopathies - pathology; Diabetic Cardiomyopathies - prevention & control; Diabetic cardiomyopathy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Inhibitors - therapeutic use; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fasudil; fibrosis; gene expression; Heart; Hemodynamics - drug effects; Hemodynamics - physiology; histopathology; hypertrophy; In Situ Nick-End Labeling; lactate dehydrogenase; lipid peroxidation; Male; Malondialdehyde - metabolism; Medical sciences; messenger RNA; Microscopy, Electron, Transmission; Myocarditis. Cardiomyopathies; Myocardium - enzymology; Myocardium - pathology; Organ Size - drug effects; Organ Size - physiology; protein synthesis; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Rho kinase; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; Streptozotocin; superoxide dismutase; Superoxide Dismutase - metabolism; tail; Toxicology
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2012.03.006

► Increased activation of Rho kinase was demonstrated in a rat model of streptozotocin-induced diabetes. ► Long-term administration of fasudil, a Rho kinase inhibitor, improved cardiac tissue damage of diabetes. ► Long-term administration of fasudil improved signs of diabetic cardiomyopathy. Inhibition of Rho kinase (ROCK) has been shown to improve diabetic-related disorders. In this study, the cardio-protective effects and potential mechanisms of fasudil, a selective ROCK inhibitor, on diabetic cardiomyopathy were investigated in a streptozotocin (STZ)-induced diabetic rat model. Eight weeks after diabetes was induced by a single tail vein injection of 60mg/kg STZ, rats were administered long-term fasudil or captopril as a control over a four-week period. Similar to the effect of captopril, fasudil treatment significantly protected against STZ-induced hemodynamic, histopathologic changes and decreased serum lactate dehydrogenase and creatine phosphokinase. Moreover, fasudil significantly down-regulated ROCK I mRNA expression and ROCK activity, reduced cardiac collagen deposition, and decreased the incidence of apoptosis and ratio of Bax/Bcl-2 protein expression. Additionally, fasudil potently elevated superoxide dismutase activity and suppressed the extent of lipid peroxidation in sera and hearts of diabetic rats. Our findings indicated that long-term treatment with fasudil could improve cardiac dysfunction, attenuate myocardial injury and prevent pathological changes in a rat model of diabetic cardiomyopathy. These effects could be attributed to regulation of antioxidative activities, suppression of myocardial hypertrophy, apoptosis, fibrosis and subsequent cardiac remodeling. These results may help to expand the clinical application of fasudil for diabetic cardiomyopathy.