title: In vivo uptake of radiolabeled MDA2, an oxidation-specific monoclonal antibody, provides an accurate measure of atherosclerotic lesions rich in oxidized LDL and is highly sensitive to their regression.
abstract: To determine whether labeled antibodies against oxidized LDL (OxLDL) offer advantages for quantifying atherosclerosis, we compared in vivo aortic uptake of (125)I-labeled MDA2, a monoclonal antibody against malondialdehyde-lysine epitopes), atherosclerotic surface area, and aortic weight in Watanabe heritable hyperlipidemic and New Zealand White rabbits and in low density lipoprotein receptor-deficient (LDLR(-/-)) and apolipoprotein E-deficient (apoE(-/-)) mice. Absolute and specific uptakes of (125)I-MDA2 were significantly greater in plaque than in normal aortas. Uptake of (125)I-MDA2 significantly correlated with aortic weight and percent atherosclerotic surface area in rabbits and mice. To assess whether (125)I-MDA2 uptake reflects changes in lesion content of OxLDL, in a separate study, extensive atherosclerosis was induced in 4 groups of LDLR(-/-) mice by feeding them a high fat/cholesterol diet for 6 months. A baseline group was euthanized at this time. The remaining groups were fed "regression" diets (chow or chow+1% vitamin E+0.05% vitamin C) or the high fat/cholesterol diet for 6 more months. When atherosclerosis was measured as percent surface area or aortic weight, there was strong progression in the high fat/cholesterol group, moderate progression in the chow group, and no progression in the chow+vitamin E+vitamin C group compared with the baseline group. The (125)I-MDA2 method also yielded a significant increase in atherosclerosis in the high fat/cholesterol group but significant decreases in the chow and chow+vitamin E+vitamin C groups. Immunocytochemistry showed fewer oxidation-specific epitopes in lesions from the chow and chow+vitamin E+vitamin C groups. Thus, the uptake of (125)I-MDA2 correlates well with traditional measures of atherosclerosis but also reflects reduced plaque OxLDL content after hypocholesterolemic intervention.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0682, USA. stsimikas@ucsd.edu
authors.forename: S
authors.initials: S
authors.lastname: Tsimikas
authors.forename: B P
authors.initials: BP
authors.lastname: Shortal
authors.forename: J L
authors.initials: JL
authors.lastname: Witztum
authors.forename: W
authors.initials: W
authors.lastname: Palinski
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000918:Antibody Specificity; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D000939:Epitopes / Q000378:metabolism; D006949:Hyperlipidemias / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008077:Lipoproteins, LDL / Q000032:analysis*; D008315:Malondialdehyde / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010084:Oxidation-Reduction; D011817:Rabbits; D011973:Receptors, LDL / Q000235:genetics*; D013194:Staining and Labeling; D014280:Triglycerides / Q000097:blood; D014810:Vitamin E / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D014280:Triglycerides; C099252:oxidized low density lipoprotein; D014810:Vitamin E; D008315:Malondialdehyde; D002784:Cholesterol