A pH-dependent phospholipase A2 contributes to loss of plasma membrane integrity during chemical hypoxia in rat hepatocytes

D. Corinne Harrison, John J. Lemasters, Brian Herman

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Previous studies have suggested that alterations in phospholipid composition of plasma membranes may underlie lethal cell injury due to hypoxic and ischemic injury. The present study was designed to determine if such alterations are due to the activation of a pH-dependent phospholipase A2. Loss of cell viability and phospholipase A2 activity measured by arachidonic acid release increased in parallel during metabolic inhibition with KCN and iodoacetate (chemical hypoxia). Acidosis (pH 6.5) and the phospholipase inhibitors dibucaine and mepacrine, delayed loss of cell viability and release of arachidonic acid to a similar extent. These findings suggest that a pH-dependent phospholipase A2 causes alterations in plasma membrane phospholipid composition after ATP-depletion which contribute to lethal cell injury.

Original languageEnglish (US)
Pages (from-to)654-659
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume174
Issue number2
DOIs
StatePublished - Jan 31 1991

Bibliographical note

Funding Information:
We have previously reported that ATP-depleted rat hepatocytes sustain plasma membrane damage characterized by the formation, growth, and coalescence of membrane blebs with eventual rupture leading to lethal cell injury (l-5). However, the mechanisms which lead to plasma membrane injury during hypoxia remain to be identified. Exposure of hepatocytes to KCN and iodoacetate, a treatment which mimics the ATP-depletion and reductive stress of hypoxic injury, causesa >95% loss of cellular ATP within 10 minutes yet cells survive for up to 60 minutes (1,3-5). Thus, the formation, enlargement and subsequent rupture of plasma membrane blebs which occurs over this period is largely ATP-independent, Accompanying ATP depletion is a drop of intracellular pH from pH 7.1-7.4 to pH 6.0-6.3 (3-5). Intracellular pH remains acidotic for 30-40 minutes but abruptly rises just before the onset of cell death. Low extracellular pH and manipulations which deepen ‘This work was supported by Grants AGO7218 and DK30874 from the National Institutes of Health, the Gustavas and Louise Pfeiffer Foundation and Grant J-1433 from the Office of Naval Research.

Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.

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