Aldose reductase-catalyzed reduction of aldehyde phospholipids.
Oxidation of unsaturated phospholipids results in the generation of aldehyde side chains that remain esterified to the phospholipid backbone. Such "core" aldehydes elicit immune responses and promote inflammation. However, the biochemical mechanisms by which phospholipid aldehydes are metabolized or detoxified are not well understood. In the studies reported here, we examined whether aldose reductase (AR), which reduces hydrophobic aldehydes, metabolizes phospholipid aldehydes. Incubation with AR led to the reduction of 5-oxovaleroyl, 7-oxo-5-heptenoyl, 5-hydroxy-6-oxo-caproyl, and 5-hydroxy-8-oxo-6-octenoyl phospholipids generated upon oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC). The enzyme also catalyzed the reduction of phospholipid aldehydes generated from the oxidation of 1-alkyl, and 1-alkenyl analogs of PAPC, and 1-palmitoyl-2-arachidonoyl phosphatidic acid or phosphoglycerol. Aldose reductase catalyzed the reduction of chemically synthesized 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine (POVPC) with a K(m) of 10 mum. Addition of POVPC to the culture medium led to incorporation and reduction of the aldehyde in COS-7 and THP-1 cells. Reduction of POVPC in these cells was prevented by the AR inhibitors sorbinil and tolrestat and was increased in COS-7 cells overexpressing AR. Together, these observations suggest that AR may be a significant participant in the metabolism of several structurally diverse phospholipid aldehydes. This metabolism may be a critical regulator of the pro-inflammatory and immunogenic effects of oxidized phospholipids.
Institute of Molecular Cardiology, Department of Medicine, 580 S. Preston St., University of Louisville, Louisville, KY 40202, USA.
Sanjay
S
Srivastava
Matthew
M
Spite
John O
JO
Trent
Matthew B
MB
West
Yonis
Y
Ahmed
Aruni
A
Bhatnagar
D000449:Aldehyde Reductase / Q000737:chemistry*; D000447:Aldehydes / Q000737:chemistry*; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D019556:COS Cells; D002384:Catalysis; D005978:Glutathione / Q000737:chemistry; D005990:Glycerol / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D015227:Lipid Peroxidation; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010712:Phosphatidic Acids / Q000737:chemistry; D010742:Phospholipid Ethers / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry
C400184:1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine; D000447:Aldehydes; D010712:Phosphatidic Acids; D010742:Phospholipid Ethers; D010743:Phospholipids; D011994:Recombinant Proteins; D000449:Aldehyde Reductase; D005978:Glutathione; D005990:Glycerol; D010100:Oxygen