title: Impact of the phosphatidylinositide 3-kinase signaling pathway on the cardioprotection induced by intermittent hypoxia.
abstract: BACKGROUND
  Exposure to intermittent hypoxia (IH) may enhance cardiac function and protects heart against ischemia-reperfusion (I/R) injury. To elucidate the underlying mechanisms, we developed a cardioprotective IH model that was characterized at hemodynamic, biochemical and molecular levels.
  
  
  METHODS
  Mice were exposed to 4 daily IH cycles (each composed of 2-min at 6-8% O2 followed by 3-min reoxygenation for 5 times) for 14 days, with normoxic mice as controls. Mice were then anesthetized and subdivided in various subgroups for analysis of contractility (pressure-volume loop), morphology, biochemistry or resistance to I/R (30-min occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion and measurement of the area at risk and infarct size). In some mice, the phosphatidylinositide 3-kinase (PI3K) inhibitor wortmannin was administered (24 µg/kg ip) 15 min before LAD.
  
  
  RESULTS
  We found that IH did not induce myocardial hypertrophy; rather both contractility and cardiac function improved with greater number of capillaries per unit volume and greater expression of VEGF-R2, but not of VEGF. Besides increasing the phosphorylation of protein kinase B (Akt) and the endothelial isoform of NO synthase with respect to control, IH reduced the infarct size and post-LAD proteins carbonylation, index of oxidative damage. Administration of wortmannin reduced the level of Akt phosphorylation and worsened the infarct size.
  
  
  CONCLUSIONS
  We conclude that the PI3K/Akt pathway is crucial for IH-induced cardioprotection and may represent a viable target to reduce myocardial I/R injury.
authors.affiliation: Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland ; Laboratorio di Biologia Vascolare e Medicina Regenerativa, Centro Cardiologico Monzino, IRCSS, Milan, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Milano
authors.forename: Provvidenza Maria
authors.initials: PM
authors.lastname: Abruzzo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bolotta
authors.forename: Marina
authors.initials: M
authors.lastname: Marini
authors.forename: Laura
authors.initials: L
authors.lastname: Terraneo
authors.forename: Barbara
authors.initials: B
authors.lastname: Ravara
authors.forename: Luisa
authors.initials: L
authors.lastname: Gorza
authors.forename: Maurizio
authors.initials: M
authors.lastname: Vitadello
authors.forename: Sabrina
authors.initials: S
authors.lastname: Burattini
authors.forename: Davide
authors.initials: D
authors.lastname: Curzi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Falcieri
authors.forename: Ludwig K
authors.initials: LK
authors.lastname: von Segesser
authors.forename: Michele
authors.initials: M
authors.lastname: Samaja
mesh_terms: D000818:Animals; D006439:Hemodynamics; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D051379:Mice; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt