Serum antibodies to oxidised low-density lipoprotein in pre-eclampsia and coronary heart disease

Armstrong, V W; Wieland, Eberhard; Diedrich, Falko; Renner, André; Rath, Werner; Kreuzer, H; Kuhn, Walther; Oellerich, Michael

doi:10.1016/s0140-6736(94)92971-8

Cited by 40 publications

(19 citation statements)

References 3 publications

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“…Stringer et al 10 reported that serum lipid peroxide levels were higher in subjects with coronary artery disease compared with controls. Similar findings have been reported for ␣-oxLDL in some, [11][12][13][14][15][16] but not all, [17][18][19] studies. Recent reports from the Physicians' Health Study 20,21 and the CHAOS (Cambridge Heart Antioxidant Study) trial 22 indicate that a high dietary intake of vitamin E is associated with decreased risk for future coronary artery disease.…”

supporting

confidence: 89%

“…[11][12][13][14][15][16][17][18][19] Most previous studies have focused on measurements of IgG ␣-oxLDL rather than IgM ␣-oxLDL. As demonstrated here, there is a relationship between IgG ␣-oxLDL and lesion lipid content, but it is weaker than the relationship observed for IgM ␣-oxLDL and could be easily confounded by the presence of subclinical atherosclerosis in control groups.…”

Section: Discussionmentioning

confidence: 99%

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Relationship Between Lipoprotein- and Oxidation-Related Variables and Atheroma Lipid Composition in Subjects Undergoing Coronary Artery Bypass Graft Surgery

Craig

Rawstron²,

Rundell³

et al. 1999

ATVB

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Abstract-The relationship between atheroma lipid composition and serum lipoprotein and oxidation measurements has not been fully explored. To address this question, we studied serum, plasma, and aortic wall specimens from 66 subjects undergoing coronary artery bypass graft surgery. The lipid composition of aortic specimens was characterized in terms of cholesterol ester and cholesterol crystal plus phospholipid by using hot-stage polarizing light microscopy; tissue oxidation status was assessed by measuring conjugated dienes.

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supporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Relationship Between Lipoprotein- and Oxidation-Related Variables and Atheroma Lipid Composition in Subjects Undergoing Coronary Artery Bypass Graft Surgery

Craig

Rawstron²,

Rundell³

et al. 1999

ATVB

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“…In a few preliminary studies in humans, higher autoantibody titers to epitopes of OxLDL have been correlated with increased atherosclerosis (12,33,34). This suggests that autoantibodies may be an indicator of the extent of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis.

Palinski

Miller

Witztum

1995

Proc. Natl. Acad. Sci. U.S.A.

546

350

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Atherosclerotic lesions contain oxidized LDL (OxLDL), immunoglobulins, and immune-competent cells. Low levels of circulating autoantibodies against malondialdehyde (MDA)-modified lysine, an epitope of OxLDL, occur in several species, and immune complexes between such autoantibodies and OxLDL are present in lesions. To study the potential role of autoantibodies against OxLDL in the atherogenic process, we prospectively hyperimmunized LDL receptor-deficient rabbits with homologous MDA-LDL and determined the effects of this intervention on the development of atherosclerosis. Immunization with MDA-LDL generated high titers of antibodies with similar specificity as naturally occurring autoantibodies. Immunized animals showed a significant reduction in the extent of atherosclerotic lesions in the aortic tree after 6.5 months, compared with "saline"-immunized controls (48% vs. 68%, P < 0.005). Immunization with keyhole limpet hemocyanin produced no change in lesion formation. Although the mechanisms by which immunization led to a protective effect are unknown, these results suggest an important role for the immune system in modulating the atherogenic process and may indicate a novel approach for inhibiting the progression of atherosclerosis.Substantial evidence indicates that oxidized LDL (OxLDL) contributes to atherogenesis by a number of mechanisms (1, 2). Furthermore, even minor modifications of LDL render it highly immunogenic (3), and circulating autoantibodies recognizing several forms of OxLDL, in particular malondialdehyde (MDA)-modified lysine, are prevalent in humans and other species (4-6). These autoantibodies are capable of binding to epitopes of OxLDL in lesions (4, 5, 7), and immunoglobulins isolated from lesions of Watanabe heritable hyperlipidemic (WHHL) rabbits and humans recognize OxLDL and are present in lesions, in part as immune complexes with OxLDL (8).It is currently unknown if the titer of autoantibodies against epitopes of OxLDL is merely an indicator of lipoprotein modification or if such autoantibodies could modulate the atherogenic process. To address this question, we hyperimmunized WHHL rabbits with homologous MDA-LDL and determined the effect of this intervention on atherosclerosis. METHODSImmunization and Antibody Determination. LDL was isolated from healthy WHHL donor rabbits by sequential ultracentrifugation in the presence of antioxidants and antiproteolytic agents and was modified with MDA (9). MDA-LDL in which 70-85% of the lysine residues were modified was used as the immunogen and for the determination of antibody titers (9). Immunization of WHHL rabbits was begun either at an age of 6 weeks or 6 months. The primary immunization consisted of a subcutaneous injection of 160 jig of MDA-LDL (protein) per kg of body weight dissolved in phosphatebuffered saline (PBS) and suspended in an equal volume of Freund's complete adjuvant. Booster immunizations consisted of antigen in Freund's incomplete adjuvant injected intramuscularly 3 and 5 weeks after the primary immunization and ...

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“…Significant plasma titers of IgG and IgM autoantibodies against epitopes of OxLDL, in particular against MDA-LDL and 4-HNE-LDL, occur in a variety of experimental animals (6,10). In preliminary studies in humans, the titers of autoantibodies to these epitopes were higher in subjects with increased cardiovascular disease or clinical manifestations of atherosclerosis (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Furthermore, in LDL receptor-negative mice fed a high cholesterol diet, we found a fourfold rise in autoantibody titers to MDA-LDL, and the titer correlated with the extent of atherosclerosis (23).…”

Section: Discussionmentioning

confidence: 99%

“…Modified apo B is highly immunogenic (5-7), and circulating autoantibodies to epitopes of oxidized LDL (OxLDL), such as MDA-lysine, have been demonstrated in the plasma of humans, rabbits, and mice (6,(8)(9)(10). A number of studies have suggested that higher titers of these autoantibodies are found in patients with increased carotid atherosclerosis, coronary artery disease, diabetes, peripheral vascular disease, hypertension, and preeclampsia (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). The autoantibodies recognize epitopes of OxLDL in atherosclerotic lesions (10,21), and are present within lesions, in part as immune complexes with Ox-LDL (22).…”

Section: Introductionmentioning

confidence: 99%

Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma.

Palinski¹,

Hörkkö²,

Miller³

et al. 1996

J. Clin. Invest.

525

446

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Many reactive products may be formed when LDL undergoes lipid peroxidation, which in turn can react with lipids, apoproteins, and proteins, generating immunogenic neoepitopes. Autoantibodies recognizing model epitopes of oxidized low density lipoprotein, such as malondialdehydelysine, occur in plasma and in atherosclerotic lesions of humans and animals. Because apo E-deficient mice develop particularly high titers of such autoantibodies, we used their spleens to clone 13 monoclonal antibodies to various epitopes of oxidized LDL ("E0 antibodies"). Binding and competitive RIAs demonstrated significant differences in fine specificity even between E0 antibodies initially selected for binding to the same screening antigen. For example, some E0 antibodies selected for binding to malondialdehyde-LDL also recognized copper oxidized LDL, acrolein-LDL, or LDL modified by arachidonic or linoleic acid oxidation products. Circulating IgG and IgM autoantibodies binding to copper-oxidized LDL, 4-hydroxynonenal-LDL, acrolein-LDL, and LDL modified with arachidonic or linoleic acid oxidation products were found in apo E-deficient mice, suggesting that the respective antigens are formed in vivo. Epitopes recognized by some of the E0 monoclonal antibodies were also found on human circulating LDL. Each of the E0 monoclonal antibodies immunostained rabbit and human atherosclerotic lesions, and some of them yielded distinct staining patterns in advanced lesions. Together, this suggests that the natural monoclonal antibodies recognize different epitopes of complex structures formed during oxidation of lipoproteins, or epitopes formed independently at different lesion sites. Our data demonstrate that a profound immunological response to a large number of different epitopes of oxidized lipoproteins occurs in vivo. The availability of "natural" monoclonal autoantibodies should facilitate the identification of specific epitopes inducing this response.( J. Clin. Invest. 1996. 98:800-814.)

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Serum antibodies to oxidised low-density lipoprotein in pre-eclampsia and coronary heart disease

Cited by 40 publications

References 3 publications

Relationship Between Lipoprotein- and Oxidation-Related Variables and Atheroma Lipid Composition in Subjects Undergoing Coronary Artery Bypass Graft Surgery

Relationship Between Lipoprotein- and Oxidation-Related Variables and Atheroma Lipid Composition in Subjects Undergoing Coronary Artery Bypass Graft Surgery

Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis.

Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma.

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