Document Detail

Rapamycin confers preconditioning-like protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes.
MedLine Citation:
PMID:  16769083     Owner:  NLM     Status:  MEDLINE    
Rapamycin (sirolimus) is an antibiotic that inhibits protein synthesis through mammalian target of rapamycin (mTOR) signaling and is used as an immunosuppressant in the treatment of organ rejection in transplant recipients. Recently, the antigrowth properties of rapamycin have been utilized for cardiovascular benefit as stents impregnated with rapamycin effectively reduce coronary restenosis. We report here a novel role of this drug in protection against ischemia/reperfusion (I/R) injury. Adult male ICR mice were treated with rapamycin (0.25 mg/kg, IP) or volume-matched DMSO (solvent for rapamycin). The hearts were subjected to 20 min of global ischemia and 30 min of reperfusion in Langendorff mode. The blocker of mitochondrial KATP channel, 5-hydroxydecanoate (5-HD, 100 microM) was given 10 min before ischemia. Infarct size in the DMSO treated group was 28.2 +/- 1.3% and was reduced to 10.1 +/- 2.8% in the rapamycin-treated mice (64% decrease, P < 0.001). 5-HD blocked the protective effect (infarct area 32.2 +/- 1.8%, P < 0.001 vs. rapamycin). The infarct limiting effect of rapamycin was not associated with improved recovery of ventricular function. We further examined the effect of rapamycin in protection against necrosis and apoptosis in adult cardiomyocytes subjected to simulated ischemia and reoxygenation. Myocytes treated with rapamycin in doses from 25-100 nM demonstrated significantly lower trypan blue-positive necrotic cells and TUNEL-positive apoptotic nuclei, supporting the protective role of drug in the intact heart. These data suggest that rapamycin induces potent preconditioning-like effect against myocardial infarction through opening of mitochondrial KATP channels. We propose that rapamycin may be a novel therapeutic strategy to limit infarction, apoptosis, and remodeling following I/R injury in the heart.
Shakil Khan; Fadi Salloum; Anindita Das; Lei Xi; George W Vetrovec; Rakesh C Kukreja
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  41     ISSN:  0022-2828     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-08-22     Completed Date:  2006-09-29     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  256-64     Citation Subset:  IM    
Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University Medical Center, Richmond, 23298, USA.
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MeSH Terms
Apoptosis / drug effects
Coronary Restenosis / drug therapy,  pathology
Immunosuppressive Agents / pharmacology*,  therapeutic use
Ischemic Preconditioning, Myocardial*
Mice, Inbred ICR
Myocardial Reperfusion Injury / drug therapy,  metabolism*,  pathology
Myocardium / metabolism*,  pathology
Myocytes, Cardiac / metabolism*,  pathology
Protein Biosynthesis
Protein Kinases / metabolism
Recovery of Function / drug effects
Signal Transduction / drug effects
Sirolimus / pharmacology*,  therapeutic use
Ventricular Function / drug effects
Grant Support
Reg. No./Substance:
0/Immunosuppressive Agents; 53123-88-9/Sirolimus; EC 2.7.-/Protein Kinases; EC 2.7.1.-/mTOR protein
Comment In:
J Mol Cell Cardiol. 2006 Aug;41(2):226-7   [PMID:  16781729 ]

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