Beneficial effects of Mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction.
OBJECTIVE
The extent of adverse myocardial remodeling contributes essentially to the prognosis after myocardial infarction (MI). In this study we investigated whether inhibition of "mammalian target of rapamycin" (mTOR) attenuates left ventricular (LV) remodeling after MI.


BACKGROUND
Therapeutic strategies to inhibit remodeling are currently limited to inhibition of neurohumoral activation. The mTOR-dependent signaling mechanisms are centrally involved in remodeling processes and provide new therapeutic opportunities.


METHODS
Everolimus (RAD) treatment was initiated on the day after or 3 days after induction of myocardial infarction (MI) in rats.


RESULTS
After 28 days, RAD-treated animals had reduced post-MI remodeling, with improved LV function and smaller LV end-diastolic diameters (8.9 + or - 0.3 mm vs. 11.4 + or - 0.2 mm, p < 0.05), end-diastolic volumes (304 + or - 30 microl vs. 414 + or - 16 microl, p < 0.05), and cardiac myocyte size (-40% vs. vehicle, p < 0.05). Infarct size was significantly reduced compared with vehicle-treated animals. The mTOR inhibition increased autophagy and concomitantly decreased proteasome activity in the border zone of the infarcted myocardium. Measurement of autophagic flux demonstrated that RAD did not decrease autophagosome clearance. When RAD treatment was initiated 3 days after MI, adverse remodeling was still attenuated and increased autophagy was still present. Sustained improvement of LV function was observed 3 months after MI, even when RAD treatment was discontinued after 1 month.


CONCLUSIONS
Inhibition of mTOR is a potential therapeutic strategy to limit infarct size and to attenuate adverse LV remodeling after MI.
Buss
Sebastian J
SJ
Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
Muenz
Sebastian
S
Riffel
Johannes H
JH
Malekar
Pratima
P
Hagenmueller
Marco
M
Weiss
Celine S
CS
Bea
Florian
F
Bekeredjian
Raffi
R
Schinke-Braun
Martina
M
Izumo
Seigo
S
Katus
Hugo A
HA
Hardt
Stefan E
SE
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D003971:Diastole / Q000502:physiology; D004452:Echocardiography; D000068338:Everolimus; D006352:Heart Ventricles / Q000000981:diagnostic imaging; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000502:physiology; D009203:Myocardial Infarction / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D016328:NF-kappa B / Q000187:drug effects; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D009320:Atrial Natriuretic Factor; D000068338:Everolimus; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C526109:Anxa3 protein, rat; C546845:mTOR protein, rat