Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids

• Published in: Journal of lipid research Vol. 52; no. 12; pp. 2209 - 2225
• Main Authors: Vladykovskaya, Elena, Ozhegov, Evgeny, Hoetker, J. David, Xie, Zhengzhi, Ahmed, Yonis, Suttles, Jill, Srivastava, Sanjay, Bhatnagar, Aruni, Barski, Oleg A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2011; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Aldehyde Reductase - metabolism; aldose reductase; Animals; Cell Line; cytokines; Cytokines - genetics; gene expression; Humans; Inflammation - metabolism; macrophages; Macrophages - drug effects; Macrophages - enzymology; Macrophages - metabolism; Mice; Oxidation-Reduction; phospholipase A2; Phospholipid Ethers - metabolism; Phospholipid Ethers - pharmacology; POVPC; Up-Regulation - drug effects; aldose reductase; macrophages; cytokines; POVPC; phospholipase A2; gene expression
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M013854

The generation of oxidized phospholipids in lipoproteins has been linked to vascular inflammation in atherosclerotic lesions. Products of phospholipid oxidation increase endothelial activation; however, their effects on macrophages are poorly understood, and it is unclear whether these effects are regulated by the biochemical pathways that metabolize oxidized phospholipids. We found that incubation of 1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) with THP-1-derived macrophages upregulated the expression of cytokine genes, including granulocyte/macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, monocyte chemotactic protein 1 (MCP-1), interleukin (IL)-1β, IL-6, and IL-8. In these cells, reagent POVPC was either hydrolyzed to lyso-phosphatidylcholine (lyso-PC) or reduced to 1-palmitoyl-2-(5-hydroxy-valeroyl)-sn-glycero-3-phosphocholine (PHVPC). Treatment with the phospholipase A2 (PLA2) inhibitor, pefabloc, decreased POVPC hydrolysis and increased PHVPC accumulation. Pefabloc also increased the induction of cytokine genes in POVPC-treated cells. In contrast, PHVPC accumulation and cytokine production were decreased upon treatment with the aldose reductase (AR) inhibitor, tolrestat. In comparison with POVPC, lyso-PC led to 2- to 3-fold greater and PHVPC 10- to 100-fold greater induction of cytokine genes. POVPC-induced cytokine gene induction was prevented in bone-marrow derived macrophages from AR-null mice. These results indicate that although hydrolysis is the major pathway of metabolism, reduction further increases the proinflammatory responses to POVPC. Thus, vascular inflammation in atherosclerotic lesions is likely to be regulated by metabolism of phospholipid aldehydes in macrophages.