title: Absence of 12/15 lipoxygenase reduces brain oxidative stress in apolipoprotein E-deficient mice.
abstract: The enzyme 12/15 lipoxygenase (12/15LO) has been implicated in the oxidative modification of lipoproteins and phospholipids in vivo. In addition, mice deficient in apolipoprotein E (ApoE-/-) are characterized by spontaneous hypercholesterolemia and a systemic increase in oxidative stress. Whereas the absence of 12/15LO reduces lipid peroxidation in the plasma and urine of ApoE-/- mice, the relative contribution of this enzyme to oxidative stress in the central nervous system remains unknown. Here, we provide the first in vivo evidence that 12/15LO modulates brain oxidative stress reactions using ApoE-/- mice crossbred with 12/15LO-deficient (12/15LO-/-) mice (12/15LO-/-/ApoE-/-). In chow-fed 12-month-old 12/15LO-/-/ApoE-/- mice, the amount of brain isoprostane iPF2alpha-VI, a marker of lipid peroxidation, and carbonyls, markers of protein oxidation, were significantly reduced when compared with 12/15LO-expressing controls (12/15LO+/+/ApoE-/-). These results were observed despite the fact that cholesterol, triglyceride, and lipoprotein levels were similar to those of ApoE-/- mice. These data indicate a functional role for 12/15LO in the modulation of oxidative reactions in the central nervous system, supporting the hypothesis that inhibition of this enzymatic pathway may be a novel therapeutic target in clinical settings involving increased brain oxidative stress.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, John Morgan Building, Room 124, Philadelphia, PA 19104, USA.
authors.forename: Cinzia M
authors.initials: CM
authors.lastname: Chinnici
authors.forename: Yuemang
authors.initials: Y
authors.lastname: Yao
authors.forename: Tao
authors.initials: T
authors.lastname: Ding
authors.forename: Colin D
authors.initials: CD
authors.lastname: Funk
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency* / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency* / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D028421:Isoprostanes / Q000032:analysis; D015227:Lipid Peroxidation; D008074:Lipoproteins / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D050050:Protein Carbonylation; D014280:Triglycerides / Q000032:analysis
chemical_list: C475064:12-15-lipoxygenase; D001057:Apolipoproteins E; D028421:Isoprostanes; D008074:Lipoproteins; D014280:Triglycerides; D002784:Cholesterol; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase