PMID- 16769083
OWN - NLM
STAT- MEDLINE
DCOM- 20060929
LR  - 20220311
IS  - 0022-2828 (Print)
IS  - 0022-2828 (Linking)
VI  - 41
IP  - 2
DP  - 2006 Aug
TI  - Rapamycin confers preconditioning-like protection against ischemia-reperfusion 
      injury in isolated mouse heart and cardiomyocytes.
PG  - 256-64
AB  - 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.
FAU - Khan, Shakil
AU  - Khan S
AD  - Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth 
      University Medical Center, Richmond, 23298, USA.
FAU - Salloum, Fadi
AU  - Salloum F
FAU - Das, Anindita
AU  - Das A
FAU - Xi, Lei
AU  - Xi L
FAU - Vetrovec, George W
AU  - Vetrovec GW
FAU - Kukreja, Rakesh C
AU  - Kukreja RC
LA  - eng
GR  - HL51045/HL/NHLBI NIH HHS/United States
GR  - HL59469/HL/NHLBI NIH HHS/United States
GR  - HL79424/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Mol Cell Cardiol
JT  - Journal of molecular and cellular cardiology
JID - 0262322
RN  - 0 (Immunosuppressive Agents)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - J Mol Cell Cardiol. 2006 Aug;41(2):226-7. PMID: 16781729
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Coronary Restenosis/drug therapy/pathology
MH  - Humans
MH  - Immunosuppressive Agents/*pharmacology/therapeutic use
MH  - *Ischemic Preconditioning, Myocardial
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Myocardial Reperfusion Injury/drug therapy/*metabolism/pathology
MH  - Myocardium/*metabolism/pathology
MH  - Myocytes, Cardiac/*metabolism/pathology
MH  - Protein Biosynthesis
MH  - Protein Kinases/metabolism
MH  - Recovery of Function/drug effects
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases
MH  - Ventricular Function/drug effects
EDAT- 2006/06/14 09:00
MHDA- 2006/09/30 09:00
CRDT- 2006/06/14 09:00
PHST- 2006/01/20 00:00 [received]
PHST- 2006/03/30 00:00 [revised]
PHST- 2006/04/04 00:00 [accepted]
PHST- 2006/06/14 09:00 [pubmed]
PHST- 2006/09/30 09:00 [medline]
PHST- 2006/06/14 09:00 [entrez]
AID - S0022-2828(06)00526-8 [pii]
AID - 10.1016/j.yjmcc.2006.04.014 [doi]
PST - ppublish
SO  - J Mol Cell Cardiol. 2006 Aug;41(2):256-64. doi: 10.1016/j.yjmcc.2006.04.014.