PMID- 21600903
OWN - NLM
STAT- MEDLINE
DCOM- 20110906
LR  - 20161125
IS  - 1879-0631 (Electronic)
IS  - 0024-3205 (Linking)
VI  - 89
IP  - 1-2
DP  - 2011 Jul 4
TI  - Rapamycin (sirolimus) protects against hypoxic damage in primary heart cultures 
      via Na+/Ca2+ exchanger activation.
PG  - 7-14
LID - 10.1016/j.lfs.2011.04.017 [doi]
AB  - AIMS: Rapamycin (sirolimus) is an antibiotic that inhibits protein synthesis 
      through mammalian targeting of rapamycin (mTOR) signaling, and is used as an 
      immunosuppressant in the treatment of organ rejection in transplant recipients. 
      Rapamycin confers preconditioning-like protection against ischemic-reperfusion 
      injury in isolated mouse heart cultures. Our aim was to further define the role 
      of rapamycin in intracellular Ca(2+) homeostasis and to investigate the mechanism 
      by which rapamycin protects cardiomyocytes from hypoxic damage. MAIN METHODS: We 
      demonstrate here that rapamycin protects rat heart cultures from 
      hypoxic-reoxygenation (H/R) damage, as revealed by assays of lactate 
      dehydrogenase (LDH) and creatine kinase (CK) leakage to the medium, by MTT 
      (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) measurements, and 
      desmin immunostaining. As a result of hypoxia, intracellular calcium levels 
      ([Ca(2+)](i)) were elevated. However, treatment of heart cultures with rapamycin 
      during hypoxia attenuated the increase of [Ca(2+)](i). Rapamycin also attenuated 
      (45)Ca(2+) uptake into the sarcoplasmic reticulum (SR) of skinned heart cultures 
      in a dose- and time-dependent manner. KB-R7943, which inhibits the "reverse" mode 
      of Na(+)/Ca(2+) exchanger (NCX), protected heart cultures from H/R damage with or 
      without the addition of rapamycin. Rapamycin decreased [Ca(2+)](i) following its 
      elevation by extracellular Ca(2+) ([Ca(2+)](o)) influx, thapsigargin treatment, 
      or depolarization with KCl. KEY FINDINGS: We suggest that rapamycin induces 
      cardioprotection against hypoxic/reoxygenation damage in primary heart cultures 
      by stimulating NCX to extrude Ca(2+) outside the cardiomyocytes. SIGNIFICANCE: 
      According to our findings, rapamycin preserves Ca(2+) homeostasis and prevents 
      Ca(2+) overload via extrusion of Ca(2+) surplus outside the sarcolemma, thereby 
      protecting the cells from hypoxic stress.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - El-Ani, Dalia
AU  - El-Ani D
AD  - Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 
      Israel.
FAU - Stav, Hagit
AU  - Stav H
FAU - Guetta, Victor
AU  - Guetta V
FAU - Arad, Michael
AU  - Arad M
FAU - Shainberg, Asher
AU  - Shainberg A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110512
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 0 (2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate)
RN  - 0 (Sodium-Calcium Exchanger)
RN  - 0 (Tetrazolium Salts)
RN  - 0 (Thiazoles)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 2.7.3.2 (Creatine Kinase)
RN  - EUY85H477I (thiazolyl blue)
RN  - GYV9AM2QAG (Thiourea)
RN  - SY7Q814VUP (Calcium)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Calcium/*metabolism
MH  - Cell Hypoxia/drug effects
MH  - Cells, Cultured
MH  - Creatine Kinase/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Homeostasis/*drug effects/physiology
MH  - L-Lactate Dehydrogenase/metabolism
MH  - Rats
MH  - Reperfusion Injury/*prevention & control
MH  - Sarcoplasmic Reticulum/metabolism
MH  - Sirolimus/*pharmacology
MH  - Sodium-Calcium Exchanger/antagonists & inhibitors/*metabolism
MH  - Tetrazolium Salts
MH  - Thiazoles
MH  - Thiourea/analogs & derivatives/pharmacology
MH  - Time Factors
EDAT- 2011/05/24 06:00
MHDA- 2011/09/07 06:00
CRDT- 2011/05/24 06:00
PHST- 2011/01/19 00:00 [received]
PHST- 2011/03/29 00:00 [revised]
PHST- 2011/04/19 00:00 [accepted]
PHST- 2011/05/24 06:00 [entrez]
PHST- 2011/05/24 06:00 [pubmed]
PHST- 2011/09/07 06:00 [medline]
AID - S0024-3205(11)00200-1 [pii]
AID - 10.1016/j.lfs.2011.04.017 [doi]
PST - ppublish
SO  - Life Sci. 2011 Jul 4;89(1-2):7-14. doi: 10.1016/j.lfs.2011.04.017. Epub 2011 May 
      12.