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OxLDL induces macrophage gamma-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis.
J Lipid Res. 2001 May; 42(5):813-23.JL

Abstract

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 gamma-glutamylcysteine synthetase heavy subunit (gamma-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 gamma-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 gamma-GCS-HS induction. Acetylated LDL (AcLDL) also caused a moderate induction of gamma-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 gamma-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 gamma-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.

Authors+Show Affiliations

Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11352989

Citation

Shen, L, and A Sevanian. "OxLDL Induces Macrophage gamma-GCS-HS Protein Expression: a Role for oxLDL-associated Lipid Hydroperoxide in GSH Synthesis." Journal of Lipid Research, vol. 42, no. 5, 2001, pp. 813-23.
Shen L, Sevanian A. OxLDL induces macrophage gamma-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis. J Lipid Res. 2001;42(5):813-23.
Shen, L., & Sevanian, A. (2001). OxLDL induces macrophage gamma-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis. Journal of Lipid Research, 42(5), 813-23.
Shen L, Sevanian A. OxLDL Induces Macrophage gamma-GCS-HS Protein Expression: a Role for oxLDL-associated Lipid Hydroperoxide in GSH Synthesis. J Lipid Res. 2001;42(5):813-23. PubMed PMID: 11352989.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - OxLDL induces macrophage gamma-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis. AU - Shen,L, AU - Sevanian,A, PY - 2001/5/16/pubmed PY - 2001/8/31/medline PY - 2001/5/16/entrez SP - 813 EP - 23 JF - Journal of lipid research JO - J. Lipid Res. VL - 42 IS - 5 N2 - 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 gamma-glutamylcysteine synthetase heavy subunit (gamma-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 gamma-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 gamma-GCS-HS induction. Acetylated LDL (AcLDL) also caused a moderate induction of gamma-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 gamma-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 gamma-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. SN - 0022-2275 UR - https://www.unboundmedicine.com/medline/citation/11352989/OxLDL_induces_macrophage_gamma_GCS_HS_protein_expression:_a_role_for_oxLDL_associated_lipid_hydroperoxide_in_GSH_synthesis_ L2 - http://www.jlr.org/cgi/pmidlookup?view=long&pmid=11352989 DB - PRIME DP - Unbound Medicine ER -