title: HDL protects against ischemia reperfusion injury by preserving mitochondrial integrity.
abstract: OBJECTIVE
  High density lipoproteins (HDL) protect against ischemia reperfusion injury (IRI). However the precise mechanisms are not clearly understood. The novel intrinsic prosurvival signaling pathway named survivor activating factor enhancement (SAFE) path involves the activation of tumor necrosis factor (TNF) alpha and signal transducer and activator of transcription 3 (STAT3). SAFE plays a crucial role in cardioprotection against IRI. We propose that HDL protect against IRI via activation of the SAFE pathway and modulation of the mitochondrial permeability transition pore (mPTP) opening.
  
  
  RESULTS
  Isolated mouse hearts were subjected to global ischemia (35 min) followed by reperfusion (45 min). HDL were given during the first 7 min of reperfusion. In control hearts, the post-reperfusion infarct size was 41.3 ± 2.3%. Addition of HDL during reperfusion reduced the infarct size in a dose-dependent manner (HDL 200 μg protein/ml: 25.5 ± 1.6%, p < 0.001 vs. control). This protective effect was absent in TNF deficient mice (TNF-KO) or cardiomyocyte-STAT3 deficient mice (STAT3-KO). Similarly, HDL, given as a preconditioning stimulus, improved cell survival and inhibited mPTP opening in isolated cardiomyocytes subjected to simulated ischemia. These protective responses were inhibited in cardiomyocytes from TNF-KO and STAT3-KO mice.
  
  
  CONCLUSIONS
  Our data demonstrate that HDL protect against IRI by inhibition of mPTP opening, an effect mediated via activation of the SAFE pathway.
authors.affiliation: Division of Endocrinology, University Hospital Geneva, Geneva, Switzerland. Miguel.Frias@unige.ch
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Frias
authors.forename: Sarah
authors.initials: S
authors.lastname: Pedretti
authors.forename: Damian
authors.initials: D
authors.lastname: Hacking
authors.forename: Sarin
authors.initials: S
authors.lastname: Somers
authors.forename: Lydia
authors.initials: L
authors.lastname: Lacerda
authors.forename: Lionel H
authors.initials: LH
authors.lastname: Opie
authors.forename: Richard W
authors.initials: RW
authors.lastname: James
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lecour
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D008076:Cholesterol, HDL / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D008076:Cholesterol, HDL; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha