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

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An Erratum to this article was published on 22 September 2016

Abstract

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 ([Ca2+]i) removal and rescued expression of protein responsible for [Ca2+]i clearance. Furthermore, our study indicated that fasudil treatment normalized the phosphorylation of the PKCβ2/Akt pathway in the diabetic heart, which might be the underlying mechanism accounting for the protective effect of fasudil on [Ca2+]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 Ca2+ handling and actin remodeling. Overactivation of RhoA/ROCK plays a key role in the development of DCM. Inhibition of ROCK activity with fasudil improved [Ca2+]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 [Ca2+]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.

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Acknowledgments

We sincerely thank Lu Zhang at Zhejiang University for her excellent technical assistance for confocal microscopy.

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Authors and Affiliations

  1. Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China

    Dongwu Lai, Jing Gao, Xukun Bi, Hong He, Shaoxiang Weng, Ying Yang, Yang Ye & Guosheng Fu

  2. Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China

    Xiaolu Shi

  3. Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China

    Yu Chen

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  1. Dongwu Lai
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Correspondence to Guosheng Fu.

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Grant support

This work was supported by grants from the National Natural Science Foundation of China (No. 81100159 and 81100167), Medical and Health Science Program of Zhejiang Province (No. 201477370 and 201646246), Natural Science Foundation of Zhejiang Province (No. LY15H020003), and Health Science and Technology Plan of Hangzhou City (No. 2013A28).

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The authors declare that they have no conflict of interest.

Additional information

Dongwu Lai and Jing Gao contributed equally to this work.

An erratum to this article is available at http://dx.doi.org/10.1007/s00109-016-1476-2.

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Lai, D., Gao, J., Bi, X. et al. The Rho kinase inhibitor, fasudil, ameliorates diabetes-induced cardiac dysfunction by improving calcium clearance and actin remodeling. J Mol Med 95, 155–165 (2017). https://doi.org/10.1007/s00109-016-1469-1

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