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PRE-CLINICAL RESEARCH

Beneficial Effects of Mammalian Target of Rapamycin Inhibition on Left Ventricular Remodeling After Myocardial Infarction

Sebastian J. Buss, MD^_*, Sebastian Muenz, MD^_*, Johannes H. Riffel, MD^_*, Pratima Malekar, PhD^_*, Marco Hagenmueller, PhD^_*, Celine S. Weiss, MD^_*, Florian Bea, MD^_*, Raffi Bekeredjian, MD^_*, Martina Schinke-Braun, PhD, Seigo Izumo, MD, PhD, Hugo A. Katus, MD^_* and Stefan E. Hardt, MD^_*,_*

^_* Department of Cardiology, University of Heidelberg, Heidelberg, Germany
Novartis Institutes of Biomedical Research, Cardiovascular Research, Cambridge, Massachusetts

Manuscript received April 30, 2009; revised manuscript received August 18, 2009, accepted August 24, 2009.

^_* Reprint requests and correspondence: Dr. Stefan E. Hardt, Department of Cardiology, Angiology, and Pulmology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany (Email: stefan.hardt{at}med.uni-heidelberg.de).

Objectives: 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 ± 0.3 mm vs. 11.4 ± 0.2 mm, p < 0.05), end-diastolic volumes (304 ± 30 µl vs. 414 ± 16 µl, 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.

Key Words: hypertrophy • mTOR signaling • myocardial infarction • remodeling

Abbreviations and Acronyms   AMC = 7-amino-4-methylcoumarin   EDD = end-diastolic diameter   ESD = end-systolic diameter   LV = left ventricle/ventricular   MDC = monodansylcadaverine   MI = myocardial infarction   mTOR = mammalian target of rapamycin   NFB = nuclear factor-kappa B   RAD = everolimus   TTC = triphenyl tetrazolium chloride

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