Journal article

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

Mark T Waddingham, Amanda J Edgley, Alberto Astolfo, Tadakatsu Inagaki, Yutaka Fujii, Cheng-Kun Du, Dong-Yun Zhan, Hirotsugu Tsuchimochi, Naoto Yagi, Darren J Kelly, Mikiyasu Shirai, James T Pearson

Cardiovascular Diabetology | BMC | Published : 2015

Abstract

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 ..

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Grants

Awarded by National Cerebral and Cardiovascular Center


Awarded by Grants-in-Aid for Scientific Research


Funding Acknowledgements

Experiments were conducted on BL40XU at SPring-8 Synchrotron, Japan Synchrotron Radiation Research Institute, Hyogo, Japan (Proposals 2012B1469 and 2013B1759). This work was supported by an Intramural Research Fund (11-1-2) for Cardiovascular Diseases from the National Cerebral and Cardiovascular Center to MS and NY. The authors acknowledge travel support to MTW, AA and JTP by the International Synchrotron Access Programme (AS/IA/123 and AS/IA/133) managed by the Australian Synchrotron and funded by the Australian Government. MTW is a recipient of an Australian Postgraduate Award Scholarship from the University of Melbourne. The authors are grateful to Kathleen MacLeod and Hesham Soliman for their expert advice on Western Blotting experiments and Hiroyuki Iwamoto and Koki Aoyama for their assistance at BL40XU.