title: Effects of exercise training and RhoA/ROCK inhibition on plaque in ApoE-/- mice.
abstract: BACKGROUND
  The molecular mechanisms of exercise-induced cardioprotection are poorly understood. We recently reported that exercise training down-regulated gene expression of the Ras homolog gene family member A (RhoA). RhoA and its first effectors, the Rho-kinases (ROCK), have already been implicated in the pathogenesis of cardiovascular disease. The aim of this study was to compare the effects of a RhoA/ROCK inhibitor (fasudil) and exercise in the Apolipoprotein E knockout (ApoE(-/-)) mouse model of atherosclerosis.
  
  
  METHODS
  Four groups of 14 week old ApoE(-/-) mice were randomised as follows (n=12/group): i) sedentary controls (Cont); ii) fasudil (Fas) treatment (100mg/kg bodyweight/day) for 8 weeks; iii) exercise intervention (Ex:free access to running wheel for 8 weeks) and iv) exercise intervention and fasudil treatment (ExFas) for 8 weeks.
  
  
  RESULTS
  Phosphorylation of myosin light chain was significantly reduced in the brachiocephalic artery of all treatment groups compared with sedentary controls, implying an inhibitory effect of exercise and fasudil on the RhoA/ROCK pathway. Furthermore, atherosclerotic lesions were significantly smaller in all treatment and intervention groups compared with the control group (Fas: 34.7%, Ex: 48.3%, ExFas: 40.9% less than Control). The intima:media ratio was reduced by both exercise intervention and fasudil treatment alone or in combination (Fas: 23.6%, Ex: 35.5%, ExFas: 43.9% less than Control). Exercise alone and fasudil treatment alone also showed similar effects on plaque composition, increasing both smooth muscle cell and macrophage density.
  
  
  CONCLUSIONS
  These results suggest that the protective effects of exercise on atherogenesis are similar to the inhibitory effects on the RhoA/ROCK signalling pathway.
authors.affiliation: School of Human Movement Studies, The University of Queensland, Brisbane, Queensland, Australia. aya.matsumoto@uqconnect.edu.au
authors.forename: Aya
authors.initials: A
authors.lastname: Matsumoto
authors.forename: Helga D
authors.initials: HD
authors.lastname: Manthey
authors.forename: Susan A
authors.initials: SA
authors.lastname: Marsh
authors.forename: Robert G
authors.initials: RG
authors.lastname: Fassett
authors.forename: Judy B
authors.initials: JB
authors.lastname: de Haan
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Rolfe
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Coombes
mesh_terms: D000818:Animals; D001057:Apolipoproteins E; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010805:Physical Conditioning, Animal / Q000379:methods* / Q000502:physiology; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000201:enzymology* / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D016896:Treatment Outcome; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D001057:Apolipoproteins E; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein