title: Atorvastatin-induced cardioprotection of human myocardium is mediated by the inhibition of mitochondrial permeability transition pore opening via tumor necrosis factor-α and Janus kinase/signal transducers and activators of transcription pathway.
abstract: BACKGROUND
  The role of tumor necrosis factor-α (TNF-α), Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and mitochondrial Permeability Transition Pore in atorvastatin-induced cardioprotection were examined in human myocardium, in vitro.
  
  
  METHODS
  Isometric force of contraction of human right atrial trabeculae was recorded during 30-min hypoxia and 60-min reoxygenation (control) and in the presence of atorvastatin (0.1 µM, 1 µM, 10 µM). In early reoxygenation, the TNF-α inhibitor, AG490 (inhibitor of JAK/STAT), or atractyloside (mitochondrial Permeability Transition Pore opener), were administered. Cyclosporine A (inhibitor of mitochondrial Permeability Transition Pore opening) was administered during the first minute of reoxygenation alone or in presence of atorvastatin and TNF-α inhibitor or AG490. The force of contraction (percentage of baseline) at the end of reoxygenation period was compared (mean ± SD; n = 6 in each group). Protein expression of JAK/STAT pathway was measured using Western immunoblotting.
  
  
  RESULTS
  Atorvastatin 0.1 µM (70 ± 9%), 1 µM (85 ± 5%), 10 µM (89 ± 5%), and Cyclosporine A (87 ± 10%) improved the recovery of force of contraction at the end of reoxygenation, as compared with control (50 ± 3%). Atorvastatin 1 µM (4.64 ± 2.90 ng · ml(-1) · g(-1) of tissue) decreased the release of troponin Ic after hypoxia-reoxygenation (control: 26.34 ± 19.30 ng · ml(-1) · g(-1); P < 0.001). The enhanced recovery of force of contraction after atorvastatin administration was abolished by TNF-α inhibitor (53 ± 8%), AG490 (56 ± 7%), atractyloside (48 ± 8%). Cyclosporine A restored the atorvastatin-induced cardioprotection abolished by TNF-α inhibitor (87 ± 6%) and AG490 (83 ± 9%). Atorvastatin significantly increased the phosphorylation of JAK-2 and STAT-3, TNF-α inhibitor abolished the enhanced phosphorylation of JAK-2 and STAT-3 by atorvastatin.
  
  
  CONCLUSIONS
  Atorvastatin-induced cardioprotection involved the inhibition of the mitochondrial Permeability Transition Pore opening via the activation of TNF-α and the JAK/STAT pathway in early reoxygenation.
authors: Normandie Université, EA4650 Signalisation, Electrophysiologie et Imagerie and Centre Hospitalier Universitaire de Caen, Caen, France. sand.lemoine2@wanadoo.fr
authors: Sandrine
authors: S
authors: Lemoine
authors: Lan
authors: L
authors: Zhu
authors: Damien
authors: D
authors: Legallois
authors: Massimo
authors: M
authors: Massetti
authors: Alain
authors: A
authors: Manrique
authors: Jean-Luc
authors: JL
authors: Hanouz
mesh_terms: D000368:Aged; D000069059:Atorvastatin; D015153:Blotting, Western / Q000379:methods; D002316:Cardiotonic Agents / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006538:Heptanoic Acids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D006538:Heptanoic Acids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D000069059:Atorvastatin; D053612:Janus Kinases