RGD Reference Report - The Rho kinase inhibitor, fasudil, ameliorates diabetes-induced cardiac dysfunction by improving calcium clearance and actin remodeling. - Rat Genome Database

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

Authors: Lai, D  Gao, J  Bi, X  He, H  Shi, X  Weng, S  Chen, Y  Yang, Y  Ye, Y  Fu, G 
Citation: Lai D, etal., J Mol Med (Berl). 2016 Aug 30.
RGD ID: 11568692
Pubmed: PMID:27576917   (View Abstract at PubMed)
DOI: DOI:10.1007/s00109-016-1469-1   (Journal Full-text)

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 PKCbeta2/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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Diabetic Cardiomyopathies treatmentISOCfl1 (Rattus norvegicus)11568692; 11568692associated with Diabetes Mellitus and ExperimentalRGD 
Diabetic Cardiomyopathies treatmentIEP 11568692associated with Diabetes Mellitus and ExperimentalRGD 

Objects Annotated

Genes (Rattus norvegicus)
Cfl1  (cofilin 1)

Genes (Mus musculus)
Cfl1  (cofilin 1, non-muscle)

Genes (Homo sapiens)
CFL1  (cofilin 1)


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