title: H2O2 preconditioning modulates phase II enzymes through p38 MAPK and PI3K/Akt activation.
abstract: Ischemic preconditioning is a complex cardioprotective phenomenon that involves adaptive changes in cells and molecules and occurs in a biphasic pattern: an early phase after 1-2 h and a late phase after 12-24 h. While it is widely accepted that reactive oxygen species are strongly involved in triggering ischemic preconditiong, it is not clear if they play a major role in the early or late phase of preconditioning and which are the mechanisms involved. The present study was designed to investigate the mechanisms behind H(2)O(2)-induced cardioprotection in rat neonatal cardiomyocytes. We focused on antioxidant and phase II enzymes and their modulation by protein kinase signaling pathways and nuclear-factor-E(2)-related factor-1 (Nrf1) and Nrf2. H(2)O(2) preconditioning was able to counteract oxidative stress more effectively in the late than in the early phase of adaptation. In particular, H(2)O(2) preconditioning counteracted oxidative stress-induced apoptosis by decreasing caspase-3 activity, increasing Bcl2 expression and selectively increasing the expression and activity of antioxidant and phase II enzymes through Nrf1 and Nrf2 translocation to the nucleus. The downregulation of Nrf1 and Nrf2 by small interfering RNA reduced the expression level of phase II enzymes. Specific inhibitors of phosphatidylinositol 3-kinase/Akt and p38 MAPK activation partially reduced the cardioprotection elicited by H(2)O(2) preconditioning and the induction and activity of phase II enzymes. These findings demonstrate, for the first time, a key role for Nrf1, and not only for Nrf2, in the induction of phase II enzymes triggered by H(2)O(2) preconditioning.
authors.affiliation: Università di Bologna, Dipartimento di Biochimica "G. Moruzzi," Via Irnerio 48, 40126 Bologna, Italy. cristina.angeloni@unibo.it
authors.forename: Cristina
authors.initials: C
authors.lastname: Angeloni
authors.forename: Elisa
authors.initials: E
authors.lastname: Motori
authors.forename: Daniele
authors.initials: D
authors.lastname: Fabbri
authors.forename: Marco
authors.initials: M
authors.lastname: Malaguti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Leoncini
authors.forename: Antonello
authors.initials: A
authors.lastname: Lorenzini
authors.forename: Silvana
authors.initials: S
authors.lastname: Hrelia
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D019157:Ischemic Preconditioning, Myocardial; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051265:NF-E2-Related Factor 1 / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051265:NF-E2-Related Factor 1; D051267:NF-E2-Related Factor 2; D016877:Oxidants; D019253:Proto-Oncogene Proteins c-bcl-2; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3