title: Mechanisms involved in cardioprotective effects of pravastatin administered during reoxygenation in human myocardium in vitro.
abstract: BACKGROUND
  The authors investigated the effect of pravastatin during reoxygenation after myocardial hypoxia and examined the involvement of nitric oxide synthase, mitochondrial permeability transition pore, and expression of markers of apoptosis in human myocardium in vitro.
  
  
  METHODS
  Human atrial trabeculae were exposed to hypoxia for 30 min and reoxygenation for 60 min (control group; n = 10). Pravastatin (5, 10, 50, 75 μM; n = 6 in each group) was administered throughout the reoxygenation. In separate groups (n = 6 in each group), pravastatin 50 μM was administered in the presence of 200 μM L-NG-nitroarginine methyl ester, a nitric oxide synthase inhibitor, and 50 μM atractyloside, the mitochondrial permeability transition pore opener. The primary endpoint was the developed force of contraction at the end of reoxygenation, expressed as a percentage of baseline (mean ± SD). Protein expression of BAD, phospho-BAD, caspase 3, Pim-1 kinase, and Bcl-2 were measured using Western immunoblotting.
  
  
  RESULTS
  The administration of 10 (77 ± 5% of baseline), 50 (86 ± 6%), and 75 μM (88 ± 13%) pravastatin improved the force of contraction at the end of reoxygenation, compared with that of the control group (49 ± 11%; P < 0.001). These beneficial effects were prevented by L-NG-nitroarginine methyl ester and atractyloside. Compared with control group, the administration of 5 μM pravastatin did not modify the force of contraction. Pravastatin increased the phosphorylation of BAD, activated the expression of Pim-1 kinase and Bcl-2, and maintained the caspase 3 concentration relative to that of the respective untreated controls.
  
  
  CONCLUSIONS
  Pravastatin, administered at reoxygenation, protected the human myocardium by preventing the mitochondrial permeability transition pore opening, phosphorylating BAD, activating nitric oxide synthase, Pim-1 kinase, and Bcl-2, and preserving the myocardium against the caspase 3 activation.
authors.affiliation: Laboratory of Experimental Anesthesiology and Cellular Physiology EA3212, Faculty of Medicine, Centre Hospitalier Universitaire de Caen, France. sand.lemoine2@wanadoo.fr
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lemoine
authors.forename: Stéphane
authors.initials: S
authors.lastname: Allouche
authors.forename: Laurent
authors.initials: L
authors.lastname: Coulbault
authors.forename: Valérie
authors.initials: V
authors.lastname: Cornet
authors.forename: Massimo
authors.initials: M
authors.lastname: Massetti
authors.forename: Philippe
authors.initials: P
authors.lastname: Galera
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Gérard
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Hanouz
mesh_terms: D000368:Aged; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D009924:Organ Culture Techniques; D010101:Oxygen Consumption / Q000187:drug effects* / Q000502:physiology*; D017035:Pravastatin / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D017035:Pravastatin