Concentration-dependent wrestling between detrimental and protective effects of H(2)O(2) during myocardial ischemia/reperfusion

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 (H(2)O(2)) 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 H(2)O(2) PC and PoC showed three phases. At a low level (1 μM), H(2)O(2) 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 Cɛ (PKCɛ) remained unchanged. Consistently, the postischemic LV performance in 1 μM H(2)O(2) 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 μM), H(2)O(2) 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 PKCɛ inhibitor wortmannin or ɛV1–2. At a high level (1 mM), H(2)O(2) markedly aggravated the reperfusion injury and the oxidative stress but did not further enhance the RISK activation. In addition, 1 or 20 μM of H(2)O(2) PC did not alter cardioprotective effects of ischemic PC in postischemic contractile performance and protein oxidation. Our data suggest that the differential effects of H(2)O(2) are derived from a concentration-dependent wrestling between its detrimental stress and protective signaling.