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Superoxide radicals have a protective role during H2O2 stress.

ABSTRACT: Reactive oxygen species (ROS) consist of potentially toxic, partly reduced oxygen species and free radicals. After H(2)O(2) treatment, yeast cells significantly increase superoxide radical production. Respiratory chain complex III and possibly cytochrome b function are essential for this increase. Disruption of complex III renders cells sensitive to H(2)O(2) but not to the superoxide radical generator menadione. Of interest, the same H(2)O(2)-sensitive mutant strains have the lowest superoxide radical levels, and strains with the highest resistance to H(2)O(2) have the highest levels of superoxide radicals. Consistent with this correlation, overexpression of superoxide dismutase increases sensitivity to H(2)O(2), and this phenotype is partially rescued by addition of small concentrations of menadione. Small increases in levels of mitochondrially produced superoxide radicals have a protective effect during H(2)O(2)-induced stress, and in response to H(2)O(2), the wild-type strain increases superoxide radical production to activate this defense mechanism. This provides a direct link between complex III as the main source of ROS and its role in defense against ROS. High levels of the superoxide radical are still toxic. These opposing, concentration-dependent roles of the superoxide radical comprise a form of hormesis and show one ROS having a hormetic effect on the toxicity of another.

SUBMITTER: Thorpe GW

PROVIDER: S-EPMC3771949 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress are paradoxically implicated in myocardial ischemia/reperfusion (I/R) injury and cardioprotection. However, the precise interpretation for the dual roles of ROS and its relationship with the ER stress during I/R remain elusive. Here we investigated the concentration-dependent effects of hydrogen peroxide (H2O2) preconditioning (PC) and postconditioning (PoC) on the ER stress and prosurvival reperfusion injury salvage kinase (RISK) activation using an ex vivo rat myocardial I/R model. The effects of H2O2 PC and PoC showed three phases. At a low level (1 ?M), H2O2 exacerbated I/R-induced left ventricular (LV) contractile dysfunction and ER stress, as indicated by enhanced phosphorylation of protein kinase-like ER kinase and expressions of glucose-regulated protein 78, X-box-binding protein 1 splicing variant, TNF receptor-associated factor 2, activating transcription factor-6 cleaved 50 kDa fragment, and caspase-12 cleavage, but the I/R-induced RISK activation including protein kinase B (PKB/Akt) and protein kinase C? (PKC?) remained unchanged. Consistently, the postischemic LV performance in 1 ?M H2O2 PC and PoC groups was improved by inhibiting ER stress with 4-phenyl butyric acid but not affected by the ER stress inducer, tunicamycin. At a moderate level (10-100 ?M), H2O2 significantly improved postischemic LV performance and enhanced RISK activation, but it did no further alter the ER stress. The cardioprotection but not ER stress was abrogated with Akt or PKC? inhibitor wortmannin or ?V1-2. At a high level (1 mM), H2O2 markedly aggravated the reperfusion injury and the oxidative stress but did not further enhance the RISK activation. In addition, 1 or 20 ?M of H2O2 PC did not alter cardioprotective effects of ischemic PC in postischemic contractile performance and protein oxidation. Our data suggest that the differential effects of H2O2 are derived from a concentration-dependent wrestling between its detrimental stress and protective signaling.

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Superoxide radicals have a protective role during H2O2 stress.

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