H2O2 preconditioning modulates phase II enzymes through p38 MAPK and PI3K/Akt activation

Angeloni C, Motori E, Fabbri D, Malaguti M, Leoncini E, Lorenzini A, Hrelia S. H2O2 preconditioning modulates phase II enzymes through p38 MAPK and PI3K/Akt activation. Am J Physiol Heart Circ Physiol 300: H2196-H2205, 2011. First published April 8, 2011; doi: 10.1152/ajpheart.00934.2010.-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 H2O2-induced cardioprotection in rat neonatal cardiomyocytes. We focused on antioxidant and phase II enzymes and their modulation by protein kinase signaling pathways and nuclearfactor- E-2-related factor-1 (Nrf1) and Nrf2. H2O2 preconditioning was able to counteract oxidative stress more effectively in the late than in the early phase of adaptation. In particular, H2O2 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 H2O2 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 H2O2 preconditioning.