Abstract
Malondialdehyde, acetaldehyde, acrolein, and 4-hydroxynonenal are all products of fatty acid oxidation found in the fatty streaks of atherosclerotic arteries due to a lack of antioxidants and an increase in glycation products. Previously identified cross-links derived from these molecules have nearly always required more than one molecule of each type, although this is physiologically less likely than a reaction involving a single molecule. Here we provide indirect but strong evidence for a malondialdehyde-derived cross-link requiring just one malondialdehyde molecule to link arginine and lysine, giving 2-ornithinyl-4-methyl(1epsilon-lysyl)1,3-imidazole following a 4-day incubation of albumin with 8 mm malondialdehyde. This cross-link was identified as its partial degradation product Nepsilon-(2-carboxyl,2-aminoethane)-Nepsilon-methanoyl-lysine by NMR and mass spectrometry. Analysis of plasma from treated diabetic patients revealed that one patient levels had as high as 0.46%, 0.67% of their lysine/arginine residues modified by this cross-link, although others had lower levels. Alkaline hydrolysis of serum albumin also revealed two acid-labile malondialdehyde adducts of histidine in significant quantities, the isomers 4- and 2-ethylidene-histidine. These constituted up to 0.93% of the histidines in treated diabetic patients. Although collagen is readily cross-linked by malondialdehyde, none of these particular products could be found in incubations of collagen with malondialdehyde.
Highlights
Glycated collagen promotes the oxidation of polyunsaturated fatty acids to a myriad of reactive aldehydes [1, 2]
We have shown that MDA and acetaldehyde can react with collagen to give a potential cross-linking dihydropyridine product [3], and others [6, 7] have confirmed this finding
In addition to a major peak of unbound radioactivity, two products were reproducibly identified: peak B, which was found in both collagen, and bovine serum albumin (BSA), whereas peak C
Summary
Glycated collagen promotes the oxidation of polyunsaturated fatty acids to a myriad of reactive aldehydes [1, 2]. Other potential cross-links and MDA-derived adducts beyond -LAA commonly require more than one MDA molecule being required to form the proposed structure, even in the presence of acetaldehyde [3, 6, 7, 9] Such a reaction would be less likely under physiological conditions because MDA is at very low serum concentrations, and even in a “glycation hotspot,” the environment of an atherosclerotic plaque [10] would be competing with many other oxidized fatty acid or sugar products for reactive lysine. Blood clearance rates of even lightly glycated proteins or erythrocytes are considerably faster than normal [11, 12] This finding suggests that either the scavenger receptors will remove MDA-adducted proteins long before a second MDA can react to form any cross-linking structure or that other molecules will react with bound MDA first rather than a second MDA molecule.
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