Increased Plasma Oxidized Phospholipid:Apolipoprotein B-100 Ratio With Concomitant Depletion of Oxidized Phospholipids From Atherosclerotic Lesions After Dietary Lipid-Lowering

Abstract

Background-Oxidized phospholipids (OxPL) are pro-inflammatory. We evaluated whether changes in plasma levels of OxPL associated with apolipoprotein B-100 (apoB-100) reflect changes in OxPL content in atherosclerotic plaques during dietary-induced atherosclerosis progression and regression. Methods and Results-OxPL content was measured in plasma and immunohistochemically in aortic plaques with antibody E06 in cynomolgus monkeys and New Zealand White rabbits at baseline, after a high-fat/high-cholesterol diet and after reversion to normal chow. The OxPL/apoB ratio, representing the content of OxPL on individual apoB-100 particles, and Total apoB-OxPL (OxPL/apoB multiplied by plasma apoB levels), reflecting the OxPL content on all apoB-100 particles, were measured. Total apoB-OxPL plasma levels increased 3-fold (PϽ0.0001) during hypercholesterolemia and decreased Ϸ75% (PϽ0.0001) during reversion to normocholesterolemia. In contrast, OxPL/apoB levels decreased significantly (PϽ0.0001) during hypercholesterolemia and increased significantly (Pϭ0.0002) during reversion to normocholesterolemia. Immunostaining revealed that during atherosclerosis progression OxPL co-localized with apoB-100, whereas during regression OxPL virtually disappeared. Conclusion-In the setting of overall reduction of plasma OxPL levels after dietary lipid-lowering, increases in the OxPL/apoB ratio reflect reduced content of OxPL in atherosclerotic plaques. These data suggest that changes in the OxPL/apoB ratio may reflect early atherosclerosis regression.

Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)

“…This observation does not appear to be due to lack of circulating OxPLs, as cholesterol-and fat-fed cynomolgus monkeys with total plasma cholesterol ‫ف‬ 700 mg/dl and abundant E06-detectable OxPLs in atherosclerotic lesions also do not have E06-detectable OxPLs on Lp(a), as shown previously ( 34 ), but they do on PLG which has an intact KIV 10 LBS compared with Lp(a) ( 25 ). In addition, cynomolgus monkeys do carry OxPLs on apoB particles, as previously shown ( 34 ).…”

“…Plasma samples from bonobos ( Pan paniscus ) (n = 4), chimpanzees ( Pan troglodytes ) (n = 7), gorillas ( Gorilla gorilla ) (n = 6), and baboons ( Papio species ) (n = 3) were provided by the San Diego Wild Animal Park, and plasmas from cynomolgus monkeys ( Macaca fascicularis ) (n = 4) were obtained as previously described ( 34 ). WT C57BL/6×SJL, Apoe Ϫ / Ϫ , and Ldlr Ϫ / Ϫ mice were derived from existing mouse colonies.…”

Changes in lipoprotein(a), oxidized phospholipids, and LDL subclasses with a low-fat high-carbohydrate diet

“…We have made similar observations in cynomolgous monkeys, which have circulating Lp(a) but whose Lp(a) does not bind OxPL ( 42 ). In both the rabbit and primate studies, the increase in OxPL/ apoB in plasma was associated with reduced content of "minimally modifi ed LDL".…”

A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma

“…In individuals with low Lp[a] levels, there is a corresponding low level of OxPL/ apoB, suggesting that in the absence of Lp[a], these OxPLs do not accumulate on plasma apoB-containing lipoproteins other than to a minor degree. A similar situation exists with most animals that we have studied (32,33). For example, in mice with marked hypercholesterolemia, a situation in which OxPLs recognized by E06 are abundant in the arterial tissues (and probably elsewhere as well), the levels of OxPL/apoB in plasma are very low, and often just at the level of detection of our assay (33).…”