Abstract
Autoantibodies specific for malondialdehyde-modified LDL (MDA-LDL) represent potential biomarkers to predict cardiovascular risk. However, MDA-LDL is a high variability antigen with limited reproducibility. To identify peptide mimotopes of MDA-LDL, phage display libraries were screened with the MDA-LDL-specific IgM monoclonal Ab LRO4, and the specificity and antigenic properties of MDA mimotopes were assessed in vitro and in vivo. We identified one 12-mer linear (P1) and one 7-mer cyclic (P2) peptide carrying a consensus sequence, which bound specifically to murine and human anti-MDA monoclonal Abs. Furthermore, MDA mimotopes were found to mimic MDA epitopes on the surface of apoptotic cells. Immunization of mice with P2 resulted in the induction of MDA-LDL-specific Abs, which strongly immunostained human atherosclerotic lesions. We detected IgG and IgM autoAbs to both MDA mimotopes in sera of healthy subjects and patients with myocardial infarction and stable angina pectoris undergoing percutaneous coronary intervention, and the titers of autoAbs correlated significantly with respective Ab titers against MDA-LDL. In conclusion, we identified specific peptides that are immunological mimotopes of MDA. These mimotopes can serve as standardized and reproducible antigens that will be useful for diagnostic and therapeutic applications in cardiovascular disease.
Highlights
Autoantibodies specific for malondialdehydemodified LDL (MDA-LDL) represent potential biomarkers to predict cardiovascular risk
To generate peptide mimotopes of MDA epitopes present on MDA-LDL, peptide libraries were screened by biopanning for phages reactive with LRO4
We further confirmed the high specificity of LRO4 for MDA adducts, as binding to coated MDA-LDL was efficiently competed by increasing concentrations of soluble MDA-LDL and malondialdehyde-acetaldehyde-modified BSA (MAA-BSA), but not native LDL or unmodified BSA (Fig. 1B)
Summary
Autoantibodies specific for malondialdehydemodified LDL (MDA-LDL) represent potential biomarkers to predict cardiovascular risk. We identified specific peptides that are immunological mimotopes of MDA These mimotopes can serve as standardized and reproducible antigens that will be useful for diagnostic and therapeutic applications in cardiovascular disease.—Amir, S., K. The oxidative modification of LDL has been shown to result in the generation of various oxidation-specific epitopes (OSE) that are recognized by specific antibodies (Abs) in a haptenspecific manner. These include adducts with proteins of lipid peroxidation breakdown products, such as malondialdehyde (MDA), which forms complex condensation products, as well as the remaining “core aldehydes,” such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) [1, 2].
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