title: Heat shock protein 90 transfection reduces ischemia-reperfusion-induced myocardial dysfunction via reciprocal endothelial NO synthase serine 1177 phosphorylation and threonine 495 dephosphorylation.
abstract: OBJECTIVE
  The interaction of the heat shock protein 90 (Hsp90) with the endothelial NO synthase (eNOS) has been shown to account for a sustained production of NO in vitro. Here, we examined whether overexpression of Hsp90 in a pig model of cardiac infarct could preserve the myocardium from the deleterious effects of ischemia-reperfusion.
  
  
  RESULTS
  Percutaneous liposome-based gene transfer was performed by retroinfusion of the anterior interventricular vein before left anterior descending occlusion and reperfusion. We found that recombinant Hsp90 expression in the ischemic region of the heart led to a 33% reduction in infarct size and prevented the increase in postischemic left ventricular end diastolic pressure observed in mock-transfected animals. Regional myocardial function, assessed by subendocardial segment shortening in the infarct region, was increased in Hsp90-transfected animals at baseline and after pacing. All these effects were completely abrogated by administration of the NOS inhibitor N(G)-nitro-L-arginine methyl ester. We further documented in vivo and in cultured endothelial cells that the cardioprotective effects of Hsp90 were associated to its capacity to act as an adaptor for both the kinase Akt and the phosphatase calcineurin, thereby promoting eNOS serine 1177 phosphorylation and threonine 495 dephosphorylation, respectively.
  
  
  CONCLUSIONS
  Hsp90 is a promising target to enhance NO formation in vivo, which may efficiently reduce myocardial reperfusion injury.
authors.affiliation: Department of Medicine I, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
authors.forename: Chantal
authors.initials: C
authors.lastname: Dessy
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.forename: Philip
authors.initials: P
authors.lastname: Raake
authors.forename: Géraldine
authors.initials: G
authors.lastname: Daneau
authors.forename: Caroline
authors.initials: C
authors.lastname: Bouzin
authors.forename: Peter
authors.initials: P
authors.lastname: Boekstegers
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
mesh_terms: D000818:Animals; D016227:Benzoquinones; D019703:Calcineurin / Q000378:metabolism; D003331:Coronary Vessels; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D047029:Lactams, Macrocyclic; D008081:Liposomes; D009203:Myocardial Infarction / Q000201:enzymology / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism*; D010769:Phosphothreonine / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011809:Quinones / Q000494:pharmacology; D034421:Sus scrofa; D014162:Transfection; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008081:Liposomes; D011518:Proto-Oncogene Proteins; D011809:Quinones; D042461:Vascular Endothelial Growth Factor A; D010769:Phosphothreonine; D010768:Phosphoserine; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019703:Calcineurin; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester; C001277:geldanamycin