title: The Rho kinase inhibitor, fasudil, ameliorates diabetes-induced cardiac dysfunction by improving calcium clearance and actin remodeling.
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+]iclearance. 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+]iclearance. 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+]iremoval 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.
  
  
  
  Overactivation of RhoA/ROCK plays a key role in the development of DCM. Inhibition of ROCK activity with fasudil improved [Ca2+]iremoval 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.
authors: Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China.
authors: Dongwu
authors: D
authors: Lai
authors: Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China.
authors: Jing
authors: J
authors: Gao
authors: Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China.
authors: Xukun
authors: X
authors: Bi
authors: Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China.
authors: Hong
authors: H
authors: He
authors: Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China.
authors: Xiaolu
authors: X
authors: Shi
authors: Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China.
authors: Shaoxiang
authors: S
authors: Weng
authors: Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors: Yu
authors: Y
authors: Chen
authors: Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China.
authors: Ying
authors: Y
authors: Yang
authors: Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China.
authors: Yang
authors: Y
authors: Ye
authors: Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China. fugs163@163.com.
authors: Guosheng
authors: G
authors: Fu
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D064546:Protein Kinase C beta / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D064546:Protein Kinase C beta; C049347:fasudil; D002118:Calcium
keywords: Acting remodeling; Calcium transient; Diabetic cardiomyopathy; Fasudil; Rho kinase