Abstract
BackgroundEnvironmental changes, air pollution and ozone depletion are increasing oxidative stress, and global warming threatens health by heat stress. We now face a high risk of simultaneous exposure to heat and oxidative stress. However, there have been few studies investigating their combined adverse effects on cell viability.Principal FindingsPretreatment of hydrogen peroxide (H2O2) specifically and highly sensitized cells to heat stress, and enhanced loss of mitochondrial membrane potential. H2O2 exposure impaired the HSP40/HSP70 induction as heat shock response (HSR) and the unfolded protein recovery, and enhanced eIF2α phosphorylation and/or XBP1 splicing, land marks of ER stress. These H2O2-mediated effects mimicked enhanced heat sensitivity in HSF1 knockdown or knockout cells. Importantly, thermal preconditioning blocked H2O2–mediated inhibitory effects on refolding activity and rescued HSF1 +/+ MEFs, but neither blocked the effects nor rescued HSF1 -/- MEFs. These data strongly suggest that inhibition of HSR and refolding activity is crucial for H2O2–mediated enhanced heat sensitivity.ConclusionsH2O2 blocks HSR and refolding activity under heat stress, thereby leading to insufficient quality control and enhancing ER stress. These uncontrolled stress responses may enhance cell death. Our data thus highlight oxidative stress as a crucial factor affecting heat tolerance.
Highlights
Exposure to excess reactive oxygen species (ROS) induces oxidative stress, which is believed to be associated with various human pathologies, including aging, carcinogenesis, and neurodegenerative disorders [1,2]
Heat shock response (HSR) induces numerous heat shock proteins (HSPs), many of which are chaperone proteins that assist in protein folding and protect cellular homeostasis against heat and other stress stimuli [3,4]
Neither the p38 kinase inhibitor SB203580 nor the JNK inhibitor SP600125 affected viability (Figure 1B). These data suggest that H2O2–mediated oxidative stress sensitized T98G cells to heat, and stress kinases may be only marginally involved in the enhancing effect
Summary
Exposure to excess reactive oxygen species (ROS) induces oxidative stress, which is believed to be associated with various human pathologies, including aging, carcinogenesis, and neurodegenerative disorders [1,2]. These diseases may be developed from accumulation of oxidized cellular components, e.g., DNAs, proteins and lipids. These oxidized components are quickly repaired or eliminated, oxidation may alter their functional effects, thereby impairing various cellular processes. There have been few studies investigating their combined adverse effects on cell viability
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