Abstract:
:A preceding hypoxic insult can sensitize the cells or the organism to a subsequent, second insult. The aim of the present study was to investigate the molecular mechanism of this phenomenon (often termed 'two-hit' injury paradigm), in an in vitro model of hypoxia/oxidative stress injury in A549 epithelial cells, with special emphasis on the role of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) in the process. Pre-exposure of the cells to 24 h hypoxia significantly reduced intracellular glutathione (GSH) levels, reduced mitochondrial activity and adenosine triphosphate (ATP) levels. However pre-exposure to hypoxia failed to induce any change in PARP-1 expression and activation, DNA single‑strand breaks or plasma membrane integrity. Pre-exposure to hypoxia markedly increased the sensitivity of the cells to subsequent oxidative stress-induced DNA damage. Hydrogen peroxide (H2O2) induced a concentration-dependent increase in DNA breakage, PARP activation, depletion of intracellular ATP, inhibition of mitochondrial activity and two distinct parameters that quantify the breakdown of plasma membrane integrity (propidium iodide uptake or lactate dehydrogenase release). PARP-1 activation played a significant role in the H2O2-induced cell death response because PARP activation, depletion of intracellular ATP, inhibition of mitochondrial activity, and the breakdown of plasma membrane integrity were attenuated in cells with permanently silenced PARP-1. Based on measurement of the endogenous antioxidant GSH, we hypothesized that the mechanism of hypoxia-mediated enhancement of H2O2 involves depletion of the GSH during the hypoxic period, which renders the cells more sensitive to a subsequent DNA single‑strand break elicited by H2O2. DNA strand breakage then activates PARP-1, leading to the inhibition of mitochondrial function, depletion of ATP and cell necrosis. PARP-1 deficiency protects against the cytotoxicity, to a lesser degree, by protecting against GSH depletion during the hypoxic period, and, to a larger degree, by maintaining mitochondrial function and preserving intracellular ATP levels during the subsequent oxidative stress period.
journal_name
Int J Mol Medjournal_title
International journal of molecular medicineauthors
Erdélyi K,Pacher P,Virág L,Szabó Cdoi
10.3892/ijmm.2013.1397subject
Has Abstractpub_date
2013-08-01 00:00:00pages
339-46issue
2eissn
1107-3756issn
1791-244Xjournal_volume
32pub_type
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