PMID- 21957201
OWN - NLM
STAT- MEDLINE
DCOM- 20120319
LR  - 20211020
IS  - 1539-7262 (Electronic)
IS  - 0022-2275 (Print)
IS  - 0022-2275 (Linking)
VI  - 52
IP  - 12
DP  - 2011 Dec
TI  - Reductive metabolism increases the proinflammatory activity of aldehyde 
      phospholipids.
PG  - 2209-2225
LID - S0022-2275(20)40825-9 [pii]
LID - 10.1194/jlr.M013854 [doi]
AB  - 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)-alpha, monocyte chemotactic protein 1 (MCP-1), interleukin 
      (IL)-1beta, 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.
FAU - Vladykovskaya, Elena
AU  - Vladykovskaya E
AD  - Diabetes and Obesity Center, School of Medicine, University of Louisville, 
      Louisville, KY 40202.
FAU - Ozhegov, Evgeny
AU  - Ozhegov E
AD  - Diabetes and Obesity Center, School of Medicine, University of Louisville, 
      Louisville, KY 40202.
FAU - Hoetker, J David
AU  - Hoetker JD
AD  - Diabetes and Obesity Center, School of Medicine, University of Louisville, 
      Louisville, KY 40202.
FAU - Xie, Zhengzhi
AU  - Xie Z
AD  - Diabetes and Obesity Center, School of Medicine, University of Louisville, 
      Louisville, KY 40202.
FAU - Ahmed, Yonis
AU  - Ahmed Y
AD  - Diabetes and Obesity Center, School of Medicine, University of Louisville, 
      Louisville, KY 40202.
FAU - Suttles, Jill
AU  - Suttles J
AD  - Diabetes and Obesity Center, School of Medicine, University of Louisville, 
      Louisville, KY 40202.
FAU - Srivastava, Sanjay
AU  - Srivastava S
AD  - Diabetes and Obesity Center, School of Medicine, University of Louisville, 
      Louisville, KY 40202.
FAU - Bhatnagar, Aruni
AU  - Bhatnagar A
AD  - Diabetes and Obesity Center, School of Medicine, University of Louisville, 
      Louisville, KY 40202.
FAU - Barski, Oleg A
AU  - Barski OA
AD  - Diabetes and Obesity Center, School of Medicine, University of Louisville, 
      Louisville, KY 40202. Electronic address: o.barski@louisville.edu.
LA  - eng
GR  - RR-024489/RR/NCRR NIH HHS/United States
GR  - P20 RR024489/RR/NCRR NIH HHS/United States
GR  - AI-048850/AI/NIAID NIH HHS/United States
GR  - R01 HL059378/HL/NHLBI NIH HHS/United States
GR  - ES-17260/ES/NIEHS NIH HHS/United States
GR  - HL-893802S1/HL/NHLBI NIH HHS/United States
GR  - HL-89380/HL/NHLBI NIH HHS/United States
GR  - R01 HL095593/HL/NHLBI NIH HHS/United States
GR  - R21 AI048850/AI/NIAID NIH HHS/United States
GR  - R56 AI048850/AI/NIAID NIH HHS/United States
GR  - HL-95593/HL/NHLBI NIH HHS/United States
GR  - R01 HL089380/HL/NHLBI NIH HHS/United States
GR  - R01 AI048850/AI/NIAID NIH HHS/United States
GR  - R01 ES017260/ES/NIEHS NIH HHS/United States
GR  - HL-59378/HL/NHLBI NIH HHS/United States
GR  - R01 HL055477/HL/NHLBI NIH HHS/United States
GR  - HL-55477/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110927
PL  - United States
TA  - J Lipid Res
JT  - Journal of lipid research
JID - 0376606
RN  - 0 (1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine)
RN  - 0 (Cytokines)
RN  - 0 (Phospholipid Ethers)
RN  - EC 1.1.1.21 (Aldehyde Reductase)
SB  - IM
MH  - Aldehyde Reductase/metabolism
MH  - Animals
MH  - Cell Line
MH  - Cytokines/genetics
MH  - Humans
MH  - Inflammation/*metabolism
MH  - Macrophages/drug effects/enzymology/metabolism
MH  - Mice
MH  - Oxidation-Reduction
MH  - Phospholipid Ethers/*metabolism/*pharmacology
MH  - Up-Regulation/drug effects
PMC - PMC3220289
EDAT- 2011/10/01 06:00
MHDA- 2012/03/20 06:00
PMCR- 2012/12/01
CRDT- 2011/09/30 06:00
PHST- 2011/09/30 06:00 [entrez]
PHST- 2011/10/01 06:00 [pubmed]
PHST- 2012/03/20 06:00 [medline]
PHST- 2012/12/01 00:00 [pmc-release]
AID - S0022-2275(20)40825-9 [pii]
AID - m013854 [pii]
AID - 10.1194/jlr.M013854 [doi]
PST - ppublish
SO  - J Lipid Res. 2011 Dec;52(12):2209-2225. doi: 10.1194/jlr.M013854. Epub 2011 Sep 
      27.