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Letters |
1
Institute of General Pathology, Faculty of Medicine, University of Milan, I-20133 Milan, Italy
2
Laboratory of, Experimental Immunology, Division of Basic Science, NCI-FCRDC, Frederick, MD 21702-1201
3
Center for Cellular Pathology, Consiglio Nazionale delle Ricerche, I-20133 Milan, Italy
aAuthor for correspondence. Fax 39-02-26681092; e-mail mmcorsi{at}unimi.it.
To the Editor:
Oxidative modification of blood lipoproteins is an important risk factor in the development of some pathological states such as atherosclerosis (1)(2). One of the sources of oxidatively modified lipoproteins in blood is the interaction of native lipoproteins with active oxygen species generated by activated neutrophils and monocyte-macrophages. In vitro studies have suggested that modification of LDL by lipid peroxide products is one potential mechanism (3)(4)(5). Modification of LDL by malondialdehyde (MDA) or other lipid peroxides in vivo is a prerequisite to the formation of arterial foam cells (6), and the presence of antibodies to lipid oxidation products suggests that oxidatively modified LDL (oxLDL) is expressed in the artery wall (7). In vitro treatment with MDA can induce the expression of specific epitopes on oxLDL (8).
In the general population, antibodies to oxLDL and lipoperoxidations in plasma are correlated with a high risk of premature atherosclerosis. Individuals with Down syndrome (DS) show signs of premature aging, and several authors have proposed the DS population as an "atheroma-free model" (9)(10). Opinions differ as to which lipid or lipoprotein is the most important in predicting the development of atherosclerosis. Most studies compared subjects with DS with matched individuals admitted to the same institution for other disabling disorders or with unselected healthy controls. Simon et al. (11) found high serum cholesterol in young DS patients, but subsequent studies have not confirmed this in groups of affected individuals ranging in age from 6 to 60 years (12). Triglyceride concentrations have been reported to be decreased (10), increased (13), or unchanged (9) in patients with trisomy 21 compared with matched controls.
We studied two groups of children: 15 apparently healthy controls (8 males, 7 females; mean age, 4 years; range, 3–5 years) and 40 children with trisomy 21 (20 males, 20 females; mean age, 4.5 years; range, 2–7 years). We determined MDA by the LPO-586 assay (Oxis International), which is based on the reaction of a chromogenic reagent (10.3 mmol/L N-methyl-2-phenylindole in acetonitrile) with MDA at 45 °C (14). One molecule of MDA reacts with two molecules of the reagent to yield a stable chromophore with maximal absorbance at 586 nm. For the measurement of oxLDL antibodies in plasma, we used an ELISA (GULL; Design International, Kennebunk, ME) with purified oxLDL bound to ELISA plate wells. The colorimetric end-point is read at 405 nm. The concentration of anti-oxLDL IgG is proportional to oxLDL absorbance (15).
The DS population had high concentrations of MDA (mean ± SD, 2.97 ± 1.59 µmol/L compared with 1.41 ± 0.62 µmol/L for controls; P <0.025). In addition, we found high concentrations of anti-oxLDL antibodies (52.12 ± 18.47 activity units/mL) in DS patients, even very young ones, compared with controls (29.21 ± 5.13; P <0.000025). The chemically reactive lipids (MDA) released during lipid peroxidation convert LDL, the major carrier of plasma cholesterol, to an abnormal form, and receptor-mediated clearance of this altered LDL produces cholesteryl ester deposition in macrophage-derived foam cells of atheroma. In patients with atherosclerosis, this LDL content is increased (12). A growing body of evidence suggests that oxidative modification of LDL enhances its atherogenicity. Oxidative modification converts LDL to a form recognized by the macrophage acetyl-LDL receptor. During lipid peroxidation a variety of highly reactive aldehyde products are generated that, in turn, can form covalent bonds with protein, principally lysine residues. MDA is one of these products and readily reacts with lysine residues. MDA-LDL in the vessel wall could be the immunogen giving rise to autoantibodies in both aortic lesions and healthy aortic walls (13).
oxLDL induces an activation-related signal, which modulates the expression of growth factors, adhesion molecules, and tissue factors that stimulate vascular smooth-muscle cell proliferation and monocyte and T-cell migration. T cells are present in early atherosclerotic lesions and may constitute up to 20% of cells in the fibrous cap of advanced human lesions, but their role in atherogenesis is largely unknown (16). T-cell clones recognizing oxLDL in the presence of monocytes have been established from atherosclerotic plaques (17), and oxLDL may induce humoral immunity, as shown by the presence of oxLDL antibodies in hypercholesterolemic rabbits or atherosclerotic patients (18).
The discrepancy between the low incidence of atherosclerosis in DS patients (10) and the high risk associated with their increased lipoperoxidation and anti-oxLDL antibodies is apparent from our data and the results obtained by Bakalova et al. (19). The chronic heart disease affecting >40% of DS patients is presumably congenital (20) and unrelated to lipid oxidation. The Sh3bgr gene, recently isolated and mapped to chromosome 21 within the DS congenital heart disease minimal region (21), is expressed in the earliest stages of mouse heart development. It may yet turn out to play a role in heart morphogenesis and consequently in the pathogenesis of congenital heart disease in DS patients.
Acknowledgments
The OX-LDL reagent set was kindly supplied by Bouty SpA (Milan, Italy), and the LPO-586 reagent set was kindly supplied by Prodotti Gianni (Milan, Italy). We are grateful to E. De Simone (Hospital Cardarelli, Naples, Italy) for the control samples and to Judy Baggott for revising the language.
References
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