Malondialdehyde–acetaldehyde adduct is the dominant epitope after MDA modification of proteins in atherosclerosis

Abstract

Antibodies to malondialdehyde (MDA) modified macromolecules (adducts) have been detected in the serum of patients with atherosclerosis and correlate with the progression of this disease. However, the epitope and its formation have not been characterized. Studies have shown that excess MDA can be degraded to acetaldehyde which combines with proteins to from a stable dihydropyridine adduct. To investigate, mice were immunized with (MDA) adducts in the absence of adjuvant and showed an increase in antibodies to MDA adducts and the carrier protein as the concentration of MDA was increased. In fact, a number of the commercially available antibodies to MDA modified proteins were able to be inhibited by a chemical analogue hexyl-MAA. Also, MDA/MAA adducts were detected in the serum and aortic tissue of JCR diabetic/atherosclerotic rats. These studies determined that commercially available antibodies to MDA were shown to predominantly react with the MAA adduct and are present in the JCR model of atherosclerosis in both the serum and aortic tissue. Therefore, the immune response to MDA modified proteins is most likely to the dihydropyridine structure (predominant epitope in MAA), and suggests that MAA adducts may be playing a role in the development and/or progression of atherosclerosis.

Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine

“…We also show the prominent presence of MAA epitopes in human atherosclerotic lesions ( Fig. 10A ), confi rming recent reports ( 17,30 ). Importantly, MAA-epitopes are also prominent OSEs on apoptotic cells, as demonstrated by the binding epitopes were immunodominant.…”

“…8B ), and IL-4 and IL-10 were also increased signifi cantly only in the two groups of MDA-immunized mice (supplementary lesions ( Fig. 10A , B ), confi rming similar observations recently reported by others ( 17,30 ). We have postulated that because such OSEs are proinfl ammatory [e.g., see Methods and supplementary Fig.…”

Recognition of Malondialdehyde-modified Proteins by the C Terminus of Complement Factor H Is Mediated via the Polyanion Binding Site and Impaired by Mutations Found in Atypical Hemolytic Uremic Syndrome

“…Taken together, these results give support for To test the binding of FH19 -20 to a single adduct, we synthesized hexyl-MDHDC. This compound resembles the MDHDC adduct in a side chain of lysine (9) and has been shown earlier to inhibit the binding of immunoglobulins to MDA-modified albumin (10,39). Also, in our hands, hexyl-MDHDC dose-dependently prevented the binding of the anti-MDHDC mAb to MDA-BSA, with approximately equimolar concentrations needed to reduce the binding by 50% (Fig.…”

“…1) is the major adduct with very little complex structures formed (37,43,44). If MDHDC is desired in abundance, extra acetaldehyde is needed in modifications (10). Although MDHDC has been shown in atherosclerotic aortas (34), concentrations of both MDA and acetaldehyde in serum are generally very low (45,46).…”

“…The term MAA has, however, also been used for the single structure MDHDC (Fig. 1C) (9,10). Although the most prominent one (10), MDHDC is not the only adduct formed in acetaldehyde-enhanced MDAmodification (2).…”