Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis.
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.
Gao
Xiao-Ming
XM
Experimental Cardiology Laboratory, Baker Heart Research Institute, Melbourne, Victoria, Australia. xiaoming.gao@baker.edu.au
Wong
Geoffrey
G
Wang
Binghui
B
Kiriazis
Helen
H
Moore
Xiao-Lei
XL
Su
Yi-Dan
YD
Dart
Anthony
A
Du
Xiao-Jun
XJ
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
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