Acidosis reduces neuronal apoptosis

Xu, Lijun; Glassford, Alexander J.; Giaccia, Amato J.; Giffard, Rona G.

doi:10.1097/00001756-199803300-00021

Cited by 46 publications

(27 citation statements)

References 10 publications

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“…1 This result has later been confirmed by another study that showed the protective effect of acidification on pulmonary artery endothelial cell death triggered by metabolic inhibition 2 and is in agreement with another prior report that has shown comparable results in hepatic sinusoidal endothelial cells. 3 Similar results on the protective effect of low pH have also been obtained in other cell types, including neurons, 4 hepatocytes, 5 myocardiocytes, 6 and some tumor cells, 7 kept under conditions of serum deprivation or hypoxia to induce apoptosis. Furthermore, it has been shown that repetitive brief episodes of acidification protect the heart from subsequent ischemic injury.…”

supporting

confidence: 70%

“…Nevertheless, the results of the present study provide a working hypothesis to explain the antiapoptotic effect of acidification observed in a variety of cell types and experimental conditions. 1,2,4,6,7,[35][36][37] Endothelial cells are exposed to low pH in many conditions, including ischemia and metabolic or respiratory acidosis, 38 exposure to drugs that inhibit Na ϩ -H ϩ exchange in the plasma membrane, 2 and laminar shear stress, 39 which also has a marked antiapoptotic effect on these cells. 34 Finally, because Gas6/Axl signaling may be activated by low pH in other cell types also, a potential role for this pathway may be considered in ischemic preconditioning of the heart.…”

Section: Discussionmentioning

confidence: 99%

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Acidification Prevents Endothelial Cell Apoptosis by Axl Activation

D’Arcangelo

Gaetano

Capogrossi

2002

Circulation Research

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Abstract-Prior studies have shown that acidification due to hypercarbia protects endothelial cells from serum deprivation-induced apoptosis. However, the mechanism(s) responsible for the antiapoptotic effect of acidification is still unclear. cDNA array screening was performed on human umbilical vein endothelial cells cultured in a bicarbonate medium equilibrated either with 5% CO 2 (pH 7.4) or with 20% CO 2 (pH 7.0). Tyrosine kinase receptor Axl expression was 3.3-fold higher after 6 hours at pH 7.0 compared with pH 7.4; this modulation was confirmed by reverse transcriptase-polymerase chain reaction (3.0Ϯ0.9-fold, PϽ0.03; nϭ3), Northern blot (3.6Ϯ0

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supporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Acidification Prevents Endothelial Cell Apoptosis by Axl Activation

D’Arcangelo

Gaetano

Capogrossi

2002

Circulation Research

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“…Tumor cells are also exposed to low pH, increased pressure, lack of glucose or serum, and osmotic shock (32,33). It is therefore possible that these factors have a co-operative role in inducing the phosphorylation of ATR targets like p53 serine 15 or histone H2AX.…”

Section: Resultsmentioning

confidence: 99%

ATR/ATM Targets Are Phosphorylated by ATR in Response to Hypoxia and ATM in Response to Reoxygenation

Hammond

Dorie

Giaccia

2003

Journal of Biological Chemistry

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267

233

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The ATR kinase phosphorylates both p53 and Chk1 in response to extreme hypoxia (oxygen concentrations of less than 0.02%). In contrast to ATR, loss of ATM does not affect the phosphorylation of these or other targets in response to hypoxia. However, hypoxia within tumors is often transient and is inevitably followed by reoxygenation. We hypothesized that ATR activity is induced under hypoxic conditions because of growth arrest and ATM activity increases in response to the oxidative stress of reoxygenation. Using the comet assay to detect DNA damage, we find that reoxygenation induced significant amounts of DNA damage. Two ATR/ATM targets, p53 serine 15 and histone H2AX, were both phosphorylated in response to hypoxia in an ATR-dependent manner. These phosphorylations were then maintained in response to reoxygenation-induced DNA damage in an ATM-dependent manner. The reoxygenation-induced p53 serine 15 phosphorylation was inhibited by the addition of N-acetyl-L-cysteine (NAC), indicating that free radical-induced DNA damage was mediated by reactive oxygen species. Taken together these data implicate both ATR and ATM as critical roles in the response of hypoxia and reperfusion in solid tumors.

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“…In hypoxic neuronal cultures extracellular acidity in the range 6.0-7.0 has been found by some to reduce both apoptosis (Xu et al 1998) and NMDA receptor-mediated toxicity (Giffard et al 1990), while others have found it to either augment AMPA-kainate receptor-mediated toxicity (McDonald et al 1998), or simply be injurious instead of protective (Ding et al 2000). It is possible that extracellular pH values in our slices were lower than pH i values in the better buffered intracellular space, and therefore outside the ranges used in other studies.…”

Section: Nmr Detection Of Energy Restoration During Apoptosismentioning

confidence: 99%

Cytochrome c associated apoptosis during ATP recovery after hypoxia in neonatal rat cerebrocortical slices

Hirai

Sugawara

Chan

et al. 2002

Journal of Neurochemistry

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Cellular injury was evaluated in superfused cerebrocortical slices (350 lm) from 7-day-old Sprague-Dawley rats exposed to 30 min hypoxia followed by 4 h of reoxygenation. At the end of hypoxia homogenous cytosolic immunoreactivity of cytochrome c increased approximately fourfold, cytochrome c intensity in western blot analyses increased more than fivefold, and whole cell and cytosolic cleaved caspase-9 underwent 50% and 100% increases, respectively. Immunostaining of sections taken 1.5 h after hypoxia showed: (i) more than a threefold increase in cleaved caspase-9; (ii) localization of cleaved caspase-9 to the interior and peripheral exterior of nuclei; and (iii) homogeneously distributed cytochrome c in the cytosol. Western blot analysis for 1.5 h after hypoxia showed that cytosolic caspase-9 returned to control values, while whole cell caspase-9 stayed approximately the same, suggesting translocation of caspase-9 to nuclei. By 4 h after hypoxia there was significant nuclear fragmentation and an increase in TUNEL positive staining. 31 P/ 1 H nuclear magnetic resonance (NMR) confirmed substantial decreases of ATP and phosphocreatine during hypoxia, with rapid but incomplete recovery being close to steady state 1 h after reoxygenation. At all time points after hypoxia the primary injury was cytochrome c associated apoptosis. Keywords: apoptosis, ATP, brain slice, cytochrome c, hypoxia, nuclear magnetic resonance. Hypoxia is known to lead to mitochondrial release of cytochrome c to the cytosol, thereby initiating mitochondrial governance of the apoptotic cascade, or Ôintrinsic pathwayÕ apoptosis (Green and Reed 1998;Murphy et al. 1999). In this cascade, cytochrome c binds to the scaffold protein Apaf-1 in a reaction that requires deoxy-ATP (dATP), after which procaspase-9 attaches, forming a complex known as the apoptosome. Procaspase-9 has generally been regarded as a cytosolic protein. However, in many types of neurons it is found in the mitochondrial intermembrane space and also released to the cytosol during hypoxia (Krajewski et al. 1999). Apoptosis occurs after bound procaspase-9 is cleaved to become activated caspase-9 by a mechanism requiring ATP hydrolysis (Zou et al. 1997(Zou et al. , 1999Kuida 2000). Studies by others (Fujimura et al. 1998;Sugawara et al. 1999;Noshita et al. 2001) imply that hypoxia in our superfused brain slice preparation should cause substantial mitochondrial release of cytochrome c followed by extensive apoptosis. Respiring, superfused brain slices are well suited for ATPrelated mechanistic studies of hypoxia because nuclear magnetic resonance (NMR) spectroscopy can be used to continually monitor energy metabolites and it is convenient to rapidly obtain tissue for immunochemical and immunohistochemical measures. We therefore decided to use our brain slice model to investigate and compare posthypoxic time courses of cytosolic cytochrome c levels, associated apoptosis, and mitochondrial function, with the latter being assessed Abbreviations used: BSA, bovine serum albumin; DAP...

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Acidosis reduces neuronal apoptosis

Cited by 46 publications

References 10 publications

Acidification Prevents Endothelial Cell Apoptosis by Axl Activation

Acidification Prevents Endothelial Cell Apoptosis by Axl Activation

ATR/ATM Targets Are Phosphorylated by ATR in Response to Hypoxia and ATM in Response to Reoxygenation

Cytochrome c associated apoptosis during ATP recovery after hypoxia in neonatal rat cerebrocortical slices

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