title: Atorvastatin and myocardial reperfusion injury: new pleiotropic effect implicating multiple prosurvival signaling.
abstract: We investigated the potential role of atorvastatin, given at reperfusion, to improve survival of the ischemic/reperfused myocardium by activation of p44/42 MAPK and p38 MAPK with its downstream effector, HSP27. We have previously shown that atorvastatin attenuates lethal reperfusion-induced injury via activation of the phosphatidyl inositol 3-kinase (PI3K) prosurvival signaling pathway. In this study we hypothesize that other prosurvival kinases may also be implicated in this protection. Langendorff-perfused mouse hearts were subjected to 35 minutes of global ischemia followed by 30 minutes of reperfusion, and either infarct size or the levels of phosphorylated AKT, p44/42 MAPK, p38 MAPK, and HSP27 were analyzed. Atorvastatin was administered during reperfusion only. We used wortmannin to block PI3K/AKT, U0126 to block p44/42 MAPK, and SB203580 to prevent the phosphorylation of p38 MAPK and HSP27. Atorvastatin significantly reduced infarct size (32.96 +/- 3.4% versus 51.27 +/- 2.79% in controls, P < 0.05). This protection was abrogated by wortmannin (48.38 +/- 4.28%), U0126 (52.58 +/- 7.58), and SB203580 (49.37 +/- 4.16%). Western blot analysis confirmed significant phosphorylation of AKT, p44/42 MAPK, p38 MAPK, and HSP27 following administration of atorvastatin during reperfusion and abrogation of the respective phosphorylation in the presence of their specific inhibitors. Atorvastatin given at reperfusion attenuates lethal reperfusion-induced injury by the phosphorylation of multiple prosurvival pathways involving not only PI3K/AKT but also p44/42 MAPK, p38 MAPK, and HSP27.
authors.affiliation: Hatter Institute and Centre for Cardiology, University College London Hospitals and Medical School, London, United Kingdom.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Efthymiou
authors.forename: Mihaela M
authors.initials: MM
authors.lastname: Mocanu
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D003720:Densitometry; D006360:Heat-Shock Proteins / Q000502:physiology; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D011758:Pyrroles / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D006360:Heat-Shock Proteins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D000069059:Atorvastatin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases