Concentration-dependent wrestling between detrimental and protective effects of H2O2 during myocardial ischemia/reperfusion

Abstract

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 μM), 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 Cɛ (PKCɛ) remained unchanged. Consistently, the postischemic LV performance in 1 μM 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 μM), 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 PKCɛ inhibitor wortmannin or ɛV1–2. 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 μM 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.

Triptolide Attenuates Myocardial Ischemia/Reperfusion Injuries in Rats by Inducing the Activation of Nrf2/HO-1 Defense Pathway

“…MDA malondialdehyde, GSH glutathione, SOD superoxide dismutase, GPx glutathione peroxidase Cell apoptosis/death-related tissue infarct and impaired cardiac functions are linked to oxidative stress in experimental I/R injuries [32]. Excessive generation of reactive oxygen species (ROS) during oxidative stress can initiate lipid peroxidation, oxidize proteins to inactive states, cause DNA damage and finally exacerbate I/R injury [17,33], and thus, timely elimination of excess ROS is thought to be beneficial. Since measures of ROS are difficult, the end products of free radical-mediated oxidative processes, such as MDA, are used to estimate ROS content [34].…”

“…Since inflammation and oxidative stress are implicated in myocardial I/R injuries [16,17], the production of pro-inflammatory cytokines and oxidative stress-related factors was examined. We also investigated the potential regulatory mechanisms by which triptolide exerted its effects, with an emphasis on Nrf2/heme oxygenase-1 (HO-1) signaling pathway.…”

ROS generated during early reperfusion contribute to intermittent hypobaric hypoxia-afforded cardioprotection against postischemia-induced Ca2+ overload and contractile dysfunction via the JAK2/STAT3 pathway

“…Activation or overexpression of STAT3 greatly improves the myocardial survival after I/R injury through reducing oxidative stress [9], while the knockout of STAT3 or the inhibition of JAK2 by AG490 reverses the cardioprotection induced by IPoC [8,10]. However, it is unknown whether the enhanced ROS production during early reperfusion [4,5] activates STAT3 and thus contributes to the cardioprotection. Intracellular Ca 2+ overload is the second main contributor to myocardial I/R injury [1,11].…”

“…We recently found that IHH further increases the ROS production in cardiomyocytes during early reperfusion following ischemia [4]. This increase is required for a better postischemic contractile function and smaller infarct size through the effective activation of the reperfusion injury salvage kinases (RISKs) including protein kinase B (PKB/Akt) and protein kinase C epsilon (PKCε) [4,5]. However, it is unclear whether other signaling pathways are involved in the ROStriggered cardioprotection during the early reperfusion.…”

“…An excessive generation of reactive oxygen species (ROS) during early reperfusion has been considered as a major cause of I/R injury [1], while the ROS generated also act as an essential trigger of cardioprotection afforded by ischemic preconditioning (IPC), postconditioning (IPoC) and chronic intermittent hypobaric hypoxia (IHH) adaptation [2][3][4][5]. We recently found that IHH further increases the ROS production in cardiomyocytes during early reperfusion following ischemia [4].…”