Effect of Immunization With Homologous LDL and Oxidized LDL on Early Atherosclerosis in Hypercholesterolemic Rabbits

Abstract

Although the existence of an immune response against modified lipoproteins in atherosclerosis has been observed in experimental animals as well as in humans, the precise pathophysiological relevance of these findings remains unclear. In this study we determined the effect of an immunization with homologous LDL and copper-oxidized LDL on the formation of atherosclerotic plaque in hypercholesterolemic rabbits. Immunizations were performed at the start of a cholesterol-rich diet and 3 weeks later. After 16 weeks, antibodies against oxidized LDL had developed in rabbits given hypercholesterolemic diet alone, but the titers were increased by twofold in rabbits immunized with oxidized LDL as well as in rabbits immunized with LDL, suggesting that the LDL had also become oxidized during the preparation and/or immunization procedure. Immunization with LDL and oxidized LDL reduced atherosclerotic lesions in the proximal aorta by 74% (P < .05) and 48% (P = NS), respectively. The cellular composition of the lesions was not affected by the immunizations. These results support the hypothesis that an immune response against modified LDL has a protective effect against the development of early atherosclerotic lesions.

Atherogenesis and the humoral immune response to modified lipoproteins

“…In some of these studies Apo-E deficient mice and LDL-receptor-deficient [LDLr −/− ] mice deliberately immunized with homologous malondialdehyde-LDL [MDA-LDL] showed a reduction in the development of atheromatous lesions [64,65]. Similar observations were reported in hypercholesterolemic rabbits immunized with autologous oxLDL [66]. Still, it must be noted that the data obtained in active immunization experiments is not free of contradictions.…”

“…For example, the studies carried out immunizing LDLr −/− mice with MDA-LDL showed the same "protective" effect after immunization with unmodified LDL, and the reduction in atherosclerosis development was seen in the absence of antibodies to modified LDL [67]. In hypercholesterolemic rabbits immunized with autologous oxLDL [66] antibodies to oxLDL developed spontaneously in non-immunized hypercholesterolemic control rabbits, as well as in rabbits immunized with native LDL [which actually showed the greatest "protective" effect of immunization]. Also in contradiction with the proposed protective role of oxLDL and MDA-LDL antibodies was the observation of Palinski et al who reported increased oxLDL autoantibody titers in LDLr −/− mice that were significantly correlated with the extent of atherosclerosis [68].…”

Recombinant Human Antibodies Against Aldehyde-Modified Apolipoprotein B-100 Peptide Sequences Inhibit Atherosclerosis

“…9,10 Activation of this protective immunity is associated with a marked increase in oxLDL-specific IgG. We have recently identified a large number of MDA-modified sequences in apoB-100 that are recognized by antibodies present in human plasma.…”

“…A number of studies have shown that immunization of hypercholesterolemic animals with native or oxLDL leads to a significant reduction of atherosclerosis development. 9,10 Using a library of malondialdehyde (MDA)-modified polypeptides covering the complete amino acid sequence of human apoB-100, we have recently identified a large number of epitopes recognized by antibodies present in human plasma. 11 The levels of several of these antibodies show an inverse association with plasma oxLDL, suggesting that antibodies are involved in the clearance of these particles.…”

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

“…These changes occur through an ERK1/2 MAPK-dependent mechanism (Chahine et al, 2009). Immunization with oxLDL generates antibodies to oxLDL that decrease atherosclerosis in both rabbit and mouse models (Palinski et al, 1995;Ameli et al, 1996;Freigang et al, 1998). These data suggest that LDL oxidation and intracellular MAPK signaling may play key roles in cardiovascular pathogenesis.…”