title: Rapamycin protects heart from ischemia/reperfusion injury independent of autophagy by activating PI3 kinase-Akt pathway and mitochondria K(ATP) channel.
abstract: OBJECTIVE
  The purpose of this study was to investigate potential roles of rapamycin, a macrocytic lactone produced by Streptomyces hygroscopicus, in myocardial ischemia/reperfusion (I/R) injury.
  
  
  METHODS
  Male Wistar rats were pretreated with three different doses of rapamycin (0.25, 2, and 5 mg/kg). Then, isolated rat hearts were exposed to 40 min of global ischemia followed by 120 min of reperfusion using a Langendorff apparatus. Western blot analysis was used to examine changes in the expression levels of ERK1/2 and Akt kinases and LC3 -II/I (a marker of autophagy). The area of myocardial infarction and cardiac function were evaluated.
  
  
  RESULTS
  Our results demonstrated that rapamycin mediates cardioprotection in a dose-dependent manner in isolated rat hearts during myocardial I/R injury. Significant a autophagy was induced by rapamycin during I/R. Both, the mitochondrial K(ATP)-channel blocker 5-hydroxydecanoate (5-HD) and the PI3K inhibitor LY294002 (LY) abolished the protection afforded by rapamycin completely, while the inhibitors alone did not influence the infarct size in control hearts. However, the ERK1/2 inhibitor PD98059(PD) and the blocker of autophagy 3-methyladenine (3-MA) had no effect on rapamycin-mediated cardioprtection.
  
  
  CONCLUSIONS
  Cardioprotection afforded by rapamycin involves the PI3K pathway and the activation of mitochondrial K(ATP)-channels, but is independent of rapamycin-induced autophagy. This study may have significant impact on clinical practice.
authors.affiliation: The Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, China. aini2002@163.com
authors.forename: Shu-Sen
authors.initials: SS
authors.lastname: Yang
authors.forename: You-Bin
authors.initials: YB
authors.lastname: Liu
authors.forename: Jiang-Bo
authors.initials: JB
authors.lastname: Yu
authors.forename: Ying
authors.initials: Y
authors.lastname: Fan
authors.forename: Shou-Yi
authors.initials: SY
authors.lastname: Tang
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Duan
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Run-Tao
authors.initials: RT
authors.lastname: Gan
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D002316:Cardiotonic Agents; D003326:Coronary Circulation / Q000187:drug effects; D006334:Heart Function Tests; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D051058:Oncogene Protein v-akt / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D002316:Cardiotonic Agents; D054086:KATP Channels; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D020123:Sirolimus