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

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 Ϫ/Ϫ ) and apolipoprotein E-deficient (apoE Ϫ/Ϫ ) 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 Ϫ/Ϫ 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 chowϩ1% vitamin Eϩ0.05% 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 chowϩvitamin Eϩvitamin 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 chowϩvitamin Eϩvitamin C groups. Immunocytochemistry showed fewer oxidation-specific epitopes in lesions from the chow and chowϩvitamin Eϩvitamin 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.

Percutaneous Coronary Intervention Results in Acute Increases in Oxidized Phospholipids and Lipoprotein(a)

“…One possibility is that both OxPL and Lp(a) are derived from disrupted plaque contents, inasmuch as both have been previously documented to be enriched in atherosclerotic lesions in vivo. [1][2][3]5,9,10,20 In fact, recent work in animal models demonstrates that OxLDL can be imaged noninvasively with radiolabeled oxidation-specific antibodies. 2,5 Sev- …”

“…[1][2][3][4] In animals, OxLDL within plaques is preferentially depleted in response to regression/antioxidant diets. [5][6][7] In humans, plaque specimens from carotid and coronary arteries are significantly enriched in OxLDL 1,3 and become depleted in OxLDL after treatment with statins. 8 In particular, unstable plaques appear to be preferentially enriched in OxLDL, 9,10 and OxLDL in plasma has been shown to be associated with acute coronary syndromes 9,11,12 and endothelial dysfunction.…”

Aggressive Very Low-Density Lipoprotein (VLDL) and LDL Lowering by Gene Transfer of the VLDL Receptor Combined with a Low-Fat Diet Regimen Induces Regression and Reduces Macrophage Content in Advanced Atherosclerotic Lesions in LDL Receptor-Deficient Mice

“…It has been shown that lesion regression is associated with decreased levels of oxidation epitopes present in LDL within the lesion. 46 A reduced level of oxidized lipids within the arterial wall may result in plaque regression by reducing macrophage accumulation. Aggressive lipid lowering did not affect several other features of the advanced plaque, such as calcification and the presence of cholesterol clefts.…”

Lipid Lowering Reduces Oxidative Stress and Endothelial Cell Activation in Rabbit Atheroma

“…LDL lowering decreased oxLDL content within apoB-100 -immunoreactive areas and likely limited the enhanced lipid peroxidation that occurs in hypercholesterolemia. 25 Tsimikas et al 26 demonstrated that dietary lipid lowering in hypercholesterolemic mice decreased in vivo uptake of the antibody for oxLDL (MDA2) to a greater degree than other features of atherosclerosis. These changes should mitigate EC dysfunction and inflammatory cell infiltration in atherosclerotic arteries.…”