title: Chronic Rho-kinase inhibition improves left ventricular contractile dysfunction in early type-1 diabetes by increasing myosin cross-bridge extension.
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 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.
authors.affiliation: Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia. m.waddingham@student.unimelb.edu.au.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Waddingham
authors.affiliation: Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia. aedgley@unimelb.edu.au.|Department of Physiology, Monash University, Clayton, VIC, Australia. aedgley@unimelb.edu.au.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Edgley
authors.affiliation: Australian Synchrotron, Clayton, VIC, Australia. a.astolfo@ucl.ac.uk.|Department of Medical Physics and Bioengineering, University College of London, London, England, UK. a.astolfo@ucl.ac.uk.
authors.forename: Alberto
authors.initials: A
authors.lastname: Astolfo
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan. inagaki.tadakatsu.ri@ncvc.go.jp.
authors.forename: Tadakatsu
authors.initials: T
authors.lastname: Inagaki
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan. yfujii@ncvc.go.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan. duchk@ri.ncvc.co.jp.
authors.forename: Cheng-Kun
authors.initials: CK
authors.lastname: Du
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan. dyzhan@ri.ncvc.co.jp.
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Zhan
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan. tsuchimo@ri.ncvc.go.jp.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Tsuchimochi
authors.affiliation: Japan Synchrotron Radiation Research Institute, Harima, Hyogo, Japan. yagi@spring8.or.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yagi
authors.affiliation: Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia. dkelly@medstv.unimelb.edu.au.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan. shirai@ri.ncvc.go.jp.
authors.forename: Mikiyasu
authors.initials: M
authors.lastname: Shirai
authors.affiliation: Department of Physiology, Monash University, Clayton, VIC, Australia. james.pearson@monash.edu.|Australian Synchrotron, Clayton, VIC, Australia. james.pearson@monash.edu.|Monash Biomedical Imaging Facility, Monash University, Clayton, VIC, Australia. james.pearson@monash.edu.
authors.forename: James T
authors.initials: JT
authors.lastname: Pearson
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D058065:Diabetic Cardiomyopathies / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology*; D009218:Myosins / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000199:Actins; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C578418:ROCK1 protein, rat; C580818:ROCK2 protein, rat; D054460:rho-Associated Kinases; D009218:Myosins; C049347:fasudil