The Rho kinase inhibitor, fasudil, ameliorates diabetes-induced cardiac dysfunction by improving calcium clearance and actin remodeling

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2017-02, Vol.95 (2), p.155-165
• Main Authors: Lai, Dongwu, Gao, Jing, Bi, Xukun, He, Hong, Shi, Xiaolu, Weng, Shaoxiang, Chen, Yu, Yang, Ying, Ye, Yang, Fu, Guosheng
• Format: Article
• Language: English
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - therapeutic use; Actin Depolymerizing Factors - metabolism; Actins - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Calcium - metabolism; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - physiopathology; Diabetic Cardiomyopathies - drug therapy; Diabetic Cardiomyopathies - physiopathology; Human Genetics; Internal Medicine; Male; Molecular Medicine; Myocardial Contraction - drug effects; Original Article; Phosphorylation - drug effects; Protein Kinase C beta - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Rats; Rats, Sprague-Dawley; rho-Associated Kinases - antagonists & inhibitors; Time Factors
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-016-1469-1

Previous study showed inhibition of RhoA and Rho kinase (ROCK) activity with fasudil could alleviate diabetes-induced cardiac dysfunction partially due to improvement of myocardial fibrosis. However, the effect of fasudil on intracellular calcium cycling and actin remodeling, both of which are important to regulate excitation-contract coupling, is still not fully elucidated. In this study, a diabetic cardiomyopathy model was induced by a single intraperitoneal injection of streptozotocin (STZ) in male Sprague Dawley rats. Diabetic rats were treated with fasudil or placebo for 8 weeks. We found that long-term administration of fasudil, a specific Rho kinase inhibitor, significantly ameliorated diabetes-induced contractile dysfunction both at cellular and whole organ levels. Fasudil-treated rats displayed improved diastolic intracellular calcium ([Ca 2+ ] i ) removal and rescued expression of protein responsible for [Ca 2+ ] i clearance. Furthermore, our study indicated that fasudil treatment normalized the phosphorylation of the PKCβ 2 /Akt pathway in the diabetic heart, which might be the underlying mechanism accounting for the protective effect of fasudil on [Ca 2+ ] i clearance. In addition, compared to the diabetes group, fasudil also normalized the G/F-actin ratio by preventing cofilin phosphorylation and promoted F-actin organization, suggesting a beneficial effect on actin remodeling. These findings indicate the protective effect of fasudil against diabetes-induced cardiac dysfunction via modulation of Ca 2+ handling and actin remodeling. Overactivation of RhoA/ROCK plays a key role in the development of DCM. Inhibition of ROCK activity with fasudil improved [Ca 2+ ] i removal in diabetic cardiomyocytes. Fasudil normalized the G/F-actin ratio and promoted F-actin organization. ROCK may be an excellent therapeutic target for the treatment of DCM. Key message Overactivation of RhoA/ROCK plays a key role in the development of DCM. Inhibition of ROCK activity with fasudil improved [Ca 2+ ] i removal in diabetic cardiomyocytes. Fasudil normalized the G/F-actin ratio and promoted F-actin organization. ROCK may be an excellent therapeutic target for the treatment of DCM.