title: Ischemic preconditioning inhibits mitochondrial permeability transition pore opening through the PTEN/PDE4 signaling pathway.
abstract: OBJECTIVE
  Ischemic preconditioning (IPC) induces cardioprotection against ischemia-reperfusion (IR) injury by inhibiting the mitochondrial permeability transition pore (mPTP). Here, we tested the hypothesis that IPC-induced cardioprotection is mediated by the phosphatase PTEN and PDE4 (phosphodiesterase 4).
  
  
  METHODS
  Isolated hearts from wild-type mice (WT, n = 110) and myocyte-specific PTEN-knockout mice (PKO, n = 94) were exposed to IPC or control conditions followed by IR. Subcellular fractionation was performed by sucrose gradient ultracentrifugation.
  
  
  RESULTS
  IPC limited myocardial infarct size (IS) in WT mice. The PDE4 inhibitor rolipram abolished the protective effect of IPC. However, small IS was found in PKO hearts after IR, and IPC did not decrease IS but enlarged it in PKO hearts. IPC promoted PDE4D localization to caveolin-3-enriched fractions in WT mice by increasing Akt levels at the caveolae. In PKO hearts, basal PDE4D levels were elevated at the caveolae, and IPC decreased PDE4D levels. Consistent with the subcellular PDE4D protein levels and its activity, elevation in intracellular Ca(2+) levels in the ischemic heart and opening of mPTP after IR were inhibited by IPC in WT mice, but not by IPC in PKO mice.
  
  
  CONCLUSIONS
  IPC inhibits mPTP opening by regulating the PTEN/PDE4 signaling pathway.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md., USA.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Zheng
authors.forename: Lingyun
authors.initials: L
authors.lastname: Zu
authors.forename: Lewis
authors.initials: L
authors.lastname: Becker
authors.forename: Zheqing P
authors.initials: ZP
authors.lastname: Cai
mesh_terms: D000818:Animals; D066298:In Vitro Techniques / Q000379:methods; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D058988:Phosphodiesterase 4 Inhibitors / Q000378:metabolism*; D015427:Reperfusion Injury / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D058988:Phosphodiesterase 4 Inhibitors; D051059:PTEN Phosphohydrolase