Chronic Rho-kinase inhibition improves left ventricular contractile dysfunction in early type-1 diabetes by increasing myosin cross-bridge extension

Cardiovascular Diabetology

James T Pearson¹  Mikiyasu Shirai⁶  Darren J Kelly²  Naoto Yagi⁵  Hirotsugu Tsuchimochi⁶  Dong-Yun Zhan⁶  Cheng-Kun Du⁶  Yutaka Fujii⁶  Tadakatsu Inagaki⁶  Alberto Astolfo³  Amanda J Edgley⁴  Mark T Waddingham² 

[1] Monash Biomedical Imaging Facility, Monash University, Clayton, VIC, Australia;Department of Medicine, St. Vincent’s Hospital, University of Melbourne, Melbourne, VIC, Australia;Department of Medical Physics and Bioengineering, University College of London, London, England, UK;Department of Physiology, Monash University, Clayton, VIC, Australia;Japan Synchrotron Radiation Research Institute, Harima, Hyogo, Japan;Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan

关键词: Small angle X-ray scattering;    Rho-kinase;    Sarcomere;    Myocardium;    Diabetic cardiomyopathy;    Diabetes;   

Others  :  1221205
DOI  :  10.1186/s12933-015-0256-6

 received in 2015-05-18, accepted in 2015-06-25,  发布年份 2015

【 摘 要 】

Background

Impaired actin–myosin cross-bridge (CB) dynamics correlate with impaired left ventricular (LV) function in early diabetic cardiomyopathy (DCM). Elevated expression and activity of Rho kinase (ROCK) contributes to the development of DCM. ROCK targets several sarcomeric proteins including myosin light chain 2, myosin binding protein-C (MyBP-C), troponin I (TnI) and troponin T that all have important roles in regulating CB dynamics and contractility of the myocardium. Our aim was to examine if chronic ROCK inhibition prevents impaired CB dynamics and LV dysfunction in a rat model of early diabetes, and whether these changes are associated with changes in myofilament phosphorylation state.

Methods

Seven days post-diabetes induction (65 mg/kg ip, streptozotocin), diabetic rats received the ROCK inhibitor, fasudil (10 mg/kg/day ip) or vehicle for 14 days. Rats underwent cardiac catheterization to assess LV function simultaneous with X-ray diffraction using synchrotron radiation to assess in situ CB dynamics.

Results

Compared to controls, diabetic rats developed mild systolic and diastolic dysfunction, which was attenuated by fasudil. End-diastolic and systolic myosin proximity to actin filaments were significantly reduced in diabetic rats (P < 0.05). In all rats there was an inverse correlation between ROCK1 expression and the extension of myosin CB in diastole, with the lowest ROCK expression in control and fasudil-treated diabetic rats. In diabetic and fasudil-treated diabetic rats changes in relative phosphorylation of TnI and MyBP-C were not significant from controls.

Conclusions

Our results demonstrate a clear role for ROCK in the development of LV dysfunction and impaired CB dynamics in early DCM.

【 授权许可】

   
2015 Waddingham et al.

【 图 表 】

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