title: Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis.
abstract: OBJECTIVE
  Inhibition of established left ventricular hypertrophy (LVH) and fibrosis may bring clinical benefits by reducing cardiac morbidity and mortality. The mammalian target of rapamycin, mTOR, is known to play a critical role in determining cell and organ size. We investigated whether mTOR inhibition can inhibit the chronic pressure-overload-induced LVH and fibrosis.
  
  
  METHODS
  Male FVB/N mice underwent transverse aortic constriction (TAC) for 5 weeks to allow for establishment of LVH, followed by treatment with the mTOR inhibitor, Rapamune (2 mg/kg per day, gavage), for 4 weeks. Echocardiography was used to monitor changes in LVH and function. Haemodynamic, morphometric, histological and molecular analyses were conducted.
  
  
  RESULTS
  Inhibition of mTOR by Rapamune was confirmed by a suppression of activated phosphorylation of ribosomal S6 protein and eukaryotic translation initiation factor-4E due to pressure overload. Despite a comparable degree of pressure overload between the vehicle- or Rapamune-treated TAC groups, Rapamune treatment for 4 weeks attenuated TAC-induced LVH by 46%, estimated by LV weight or myocyte size, and LV fractional shortening was also preserved versus vehicle-treated control (39 +/- 1 versus 32 +/- 2%, P < 0.05). Inhibition of established LVH by Rapamune was associated with a 38% reduction in collagen content. Moreover, altered gene expression due to pressure overload was largely restored.
  
  
  CONCLUSIONS
  Despite sustained pressure overload, inhibition of mTOR by a 4-week period of Rapamune treatment attenuates chronically established LVH and cardiac fibrosis with preserved contractile function.
authors.affiliation: Experimental Cardiology Laboratory, Baker Heart Research Institute, Melbourne, Victoria, Australia. xiaoming.gao@baker.edu.au
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Wong
authors.forename: Binghui
authors.initials: B
authors.lastname: Wang
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Moore
authors.forename: Yi-Dan
authors.initials: YD
authors.lastname: Su
authors.forename: Anthony
authors.initials: A
authors.lastname: Dart
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure; D002908:Chronic Disease; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D006339:Heart Rate; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000503:physiopathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000187:drug effects / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013318:Stroke Volume; D058570:TOR Serine-Threonine Kinases
chemical_list: D009320:Atrial Natriuretic Factor; D039561:Eukaryotic Initiation Factor-4E; D007166:Immunosuppressive Agents; D048052:Mitogen-Activated Protein Kinase 3; D018995:Myosin Heavy Chains; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D038601:Ribosomal Protein S6; D050796:STAT3 Transcription Factor; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse