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Journal of Lipid Research, Vol. 42, 813-823, May 2001
Copyright © 2001 by Lipid Research, Inc.

Original Article

OxLDL induces macrophage -GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis

Correspondence to: Alex Sevanian, To whom correspondence should be addressed., asevan{at}hsc.usc.edu (E-mail)

Oxidized LDL (oxLDL) produced a rapid depletion of intracellular glutathione (GSH) followed by an adaptive increase in J774 A.1 macrophages. OxLDL also induced a transient increase in the levels of -glutamylcysteine synthetase heavy subunit (-GCS-HS), representing the catalytic subunit of the rate-limiting enzyme for de novo GSH synthesis. The induction took place within 3 h, with maximum levels observed by 10 h of treatment. Pretreatment of oxLDL with ebselen inhibited GSH depletion and attenuated the -GCS-HS induction. OxLDL-associated lipid hydroperoxides and their decomposition product aldehydes are two major components thought to account for GSH depletion in macrophages. Ebselen pretreatment had only a minor effect on malondialdehyde levels, whereas peroxide content was essentially abolished, suggesting that oxLDL-associated hydroperoxides may mediate both GSH depletion and -GCS-HS induction. Acetylated LDL (AcLDL) also caused a moderate induction of -GCS-HS protein along with a 30% transient increase in GSH by 3;–6 h, suggesting a minor involvement of scavenger receptor-mediated signaling of GSH synthesis. However, the level of -GCS induction by AcLDL was insufficient to cause a sustained increase in GSH. Macrophages with higher glutathione peroxidase (GPx) activity experienced a more rapid and extensive depletion of GSH when treated with oxLDL under similar conditions, along with greater resistance to oxLDL- or peroxide-induced cytotoxicity.

We conclude that oxLDL-associated peroxides are primarily responsible for GSH depletion, creating an oxidizing environment required for -GCS induction and compensatory GSH synthesis. This is facilitated in cells expressing high GPx activity through a rapid depletion of GSH in the face of a peroxide challenge. — Shen, L., and A. Sevanian. OxLDL induces macrophage -GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis. J. Lipid Res. 2001. 42: 813;–823.

Supplementary key words: oxidized low density lipoprotein, -glutamylcysteine synthetase, reactive oxygen species

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