An Evaluation of the Role of Calcium in Cell Injury

Harman, Andrew W.; Maxwell, Michael J.

doi:10.1146/annurev.pa.35.040195.001021

Cited by 89 publications

(23 citation statements)

References 42 publications

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“…Research into the mechanism of oxidative cell injury is shifting away from the central association of cytosolic calcium with lethal injury to focus on adverse effects of oxidants on mitochondria [49]. Our results suggest that in AA plus CYP2E1-dependent oxidative injury, influx of extracellular calcium does not play a central role in toxicity, but that activation of phospholipase A2, promotion of the mitochondrial permeability transition and loss of mitochondrial function is a general pathway for toxicity.…”

Section: Discussionmentioning

confidence: 75%

Role of intracellular calcium and phospholipase A2 in arachidonic acid-induced toxicity in liver cells overexpressing CYP2E1

Andrés¹,

Cederbaum²

2007

Archives of Biochemistry and Biophysics

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Liver cells (HepG2 and primary hepatocytes) overexpressing CYP2E1 and exposed to arachidonic acid (AA) were previously shown to lose viability together with enhanced lipid peroxidation. These events were blocked in cells pre-incubated with antioxidants (α -tocopherol, glutathione ethyl ester), or in HepG2 cells not expressing CYP2E1. The goal of the current study was to evaluate the role of calcium and calcium-activated hydrolases in these CYP2E1-AA interactions. CYP2E1-expressing HepG2 cells treated with AA showed an early increase in cytosolic calcium and partial depletion of ionomycin-sensitive calcium stores. These changes in calcium were blocked by α -tocopherol. AA activated phospholipase A2 (PLA2) in CYP2E1-expressing liver cells, and this was inhibited by PLA2 inhibitors or α -tocopherol. PLA2 inhibitors prevented the cell death caused by AA, without affecting CYP2E1 activity or lipid peroxidation. AA toxicity and PLA2 activation were inhibited in calcium-depleted cells, but not by removal of extracellular calcium alone. Removal of extracellular calcium inhibited the early increase in cytosolic calcium caused by AA. CYP2E1 overexpressing HepG2 cells exposed to AA showed a decrease in mitochondrial membrane potential, which was prevented by the PLA2 inhibitors. These results suggest that AA-induced toxicity to CYPE1-expressing cells: (i) is associated with release of Ca 2+ from intracellular stores that depends mainly on oxidative membrane damage; (ii) is associated with activation of PLA2 that depends on intracellular calcium and lipid peroxidation; iii) does not depend on increased influx of extracellular calcium, and iv) depends on the effect of converging events (lipid peroxidation, intracellular calcium, activation of PLA2) on mitochondria to induce bioenergetic failure and necrosis. These interactions may play a role in alcohol liver toxicity, which requires polyunsaturated fatty acids, and involves induction of CYP2E1.

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Section: Discussionmentioning

confidence: 75%

Role of intracellular calcium and phospholipase A2 in arachidonic acid-induced toxicity in liver cells overexpressing CYP2E1

Andrés¹,

Cederbaum²

2007

Archives of Biochemistry and Biophysics

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“…Loss of membrane integrity due to lipid peroxidation can cause extracellular Ca 2ϩ influx (40). If this were the case, then the antioxidant, N,NЈ-diphenyl-p-phenylenediamine (DPPD), which blocks lipid peroxidation after IDAM treatment (29), should block Ca 2ϩ entry.…”

Section: Ment (Data Not Shown)mentioning

confidence: 99%

“…Intracellular Ca 2ϩ homeostasis has received considerable attention as a cell death signal and as an activator of gene expression, yet consensus has not emerged regarding its role in either process (25,26,39,40). Nevertheless, maintaining intracellular free Ca 2ϩ levels at about 100 nM in the face of 1-2 mM extracellular Ca 2ϩ is important for cell survival, and toxicant treatment generally causes an increase in free Ca 2ϩ levels (26,39).…”

mentioning

confidence: 99%

Endoplasmic Reticulum Chaperones GRP78 and Calreticulin Prevent Oxidative Stress, Ca2+ Disturbances, and Cell Death in Renal Epithelial Cells

Liu¹,

Bowes²,

Water³

et al. 1997

Journal of Biological Chemistry

357

298

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, and oxidative stress. Although activation of the ER stress response did not prevent toxicity due to Ca 2؉ influx, EGTA-AM and ruthenium red both blocked cell death suggesting that redistribution of intracellular Ca 2؉ to the mitochondria may be important in toxicity. The data support a model in which induction of ER stress proteins prevents disturbances of intracellular Ca 2؉ homeostasis, thus uncoupling toxicant exposure from oxidative stress and cell death. Multiple ER stress proteins are likely to be involved in this tolerance response.

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“…On the one hand, it has been suggested that an increase in free Ca 2ϩ is nothing more than a late event associated with loss of membrane integrity and does not contribute appreciably to oxidant-induced cell killing (7)(8)(9). On the other hand, it has been proposed that an early increase in intracellular free Ca 2ϩ exacerbates oxidative stress, damages mitochondria, activates Ca 2ϩ -dependent degradative enzymes, and disrupts the cytoskeleton, all of which play a central role in oxidant-induced cell death (5,10,11).…”

mentioning

confidence: 99%

“…TBHP treatment causes peroxidation of cellular lipids, oxidation of glutathione, loss of protein thiols, release of ER Ca 2ϩ , a general increase in cytosolic free Ca 2ϩ , a permeability transition in the mitochondrial inner membrane, and lipid peroxidation (36, 44 -47). However, the role of these perturbations in TBHP-induced cell death and in particular the role of Ca 2ϩ remains unclear (5,8,9,44). Our previous studies on the ER stress response provided new insights into cell death induced by alkylating and acylating agents (31).…”

mentioning

confidence: 99%

Endoplasmic Reticulum Stress Proteins Block Oxidant-induced Ca2+ Increases and Cell Death

Liu

Miller

Water

et al. 1998

Journal of Biological Chemistry

185

156

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Oxidants are important human toxicants. Increased intracellular free Ca 2؉ may be critical for oxidant toxicity, but this mechanism remains controversial. Furthermore, oxidants damage the endoplasmic reticulum (ER) and release ER Ca 2؉ , but the role of the ER in oxidant toxicity and Ca 2؉ regulation during toxicity is also unclear. tert-Butylhydroperoxide (TBHP), a prototypical organic oxidant, causes oxidative stress and an increase in intracellular free Ca 2؉ . Therefore, we addressed the mechanism of oxidant-induced cell death and investigated the role of ER stress proteins in Ca 2؉ regulation and cytoprotection after treating renal epithelial cells with TBHP. Prior ER stress induces expression of the ER stress proteins Grp78, Grp94, and calreticulin and rendered cells resistant to cell death caused by a subsequent TBHP challenge. Expressing antisense RNA targeted to grp78 prevents grp78 induction sensitized cells to TBHP and disrupted their ability to develop cellular tolerance. In addition, overexpressing calreticulin, another ER chaperone and Ca 2؉ -binding protein, also protected cells against TBHP. Interestingly, neither prior ER stress nor calreticulin expression prevented lipid peroxidation, but both blocked the rise in intracellular free Ca 2؉ after TBHP treatment. Loading cells with EGTA, even after peroxidation had already occurred, also prevented TBHP-induced cell death, indicating that buffering intracellular Ca 2؉ prevents cell killing. Thus, Ca 2؉ plays an important role in TBHP-induced cell death in these cells, and the ER is an important regulator of cellular Ca 2؉ homeostasis during oxidative stress. Given the importance of oxidants in human disease, it would appear that the role of ER stress proteins in protection from oxidant damage warrants further consideration.

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An Evaluation of the Role of Calcium in Cell Injury

Cited by 89 publications

References 42 publications

Role of intracellular calcium and phospholipase A2 in arachidonic acid-induced toxicity in liver cells overexpressing CYP2E1

Role of intracellular calcium and phospholipase A2 in arachidonic acid-induced toxicity in liver cells overexpressing CYP2E1

Endoplasmic Reticulum Chaperones GRP78 and Calreticulin Prevent Oxidative Stress, Ca2+ Disturbances, and Cell Death in Renal Epithelial Cells

Endoplasmic Reticulum Stress Proteins Block Oxidant-induced Ca2+ Increases and Cell Death

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