title: Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids.
abstract: 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 A(2) (PLA(2)) 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.
authors.affiliation: Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, KY 40202.
authors.forename: Elena
authors.initials: E
authors.lastname: Vladykovskaya
authors.affiliation: Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, KY 40202.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Ozhegov
authors.affiliation: Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, KY 40202.
authors.forename: J David
authors.initials: JD
authors.lastname: Hoetker
authors.affiliation: Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, KY 40202.
authors.forename: Zhengzhi
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, KY 40202.
authors.forename: Yonis
authors.initials: Y
authors.lastname: Ahmed
authors.affiliation: Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, KY 40202.
authors.forename: Jill
authors.initials: J
authors.lastname: Suttles
authors.affiliation: Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, KY 40202.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, KY 40202.
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.affiliation: Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, KY 40202. Electronic address: o.barski@louisville.edu.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Barski
mesh_terms: D000449:Aldehyde Reductase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D010742:Phospholipid Ethers / Q000378:metabolism* / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C400184:1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine; D016207:Cytokines; D010742:Phospholipid Ethers; D000449:Aldehyde Reductase