Reactions of Lipid-derived Malondialdehyde with Collagen

Abstract

Malondialdehyde is a product of fatty acid oxidation (e.g. from low density lipoprotein) implicated in the damage of proteins such as collagen in the cardiovascular system (Chio, K. J., and Tappel, A. L. (1969) Biochemistry 8, 2821-2827). Its concentration is raised in diabetic subjects probably as a side effect of increased protein glycation. Collagen has enzyme-catalyzed cross-links formed between its individual molecules that are essential for maintaining the structure and flexibility of the collagen fiber. The cross-link dehydro-hydroxylysinonorleucine reacts irreversibly with 10 mM malondialdehyde at least 3 orders of magnitude faster than glucose reactions with lysine or arginine, such that there is little cross-link left after 1 h at 37°C. Other cross-links and glycated elements of collagen are also vulnerable. Several possible products of malondialdehyde with collagen cross-links are proposed, and the potential involvement of collagenous histidine in these reactions is discussed. We have also isolated N ␦ -(2-pyrimidyl)-L-ornithine from collagenous arginine reacted with malondialdehyde. The yields of this product were considerably higher than those from model reactions, being approximately 2 molecules/collagen molecule after 1 day at 37°C in 10 mM malondialdehyde. Collagenous lysine-derived malondialdehyde products may have been present but were not protected from protein acid hydrolysis by standard reduction techniques, thus resulting in a multitude of fragmented products.Glycated collagen has been shown to promote the oxidation of polyunsaturated fatty acids, adding to their typical fragmentation to a broad range of reactive compounds (1). The two major products are malondialdehyde (MDA) 1 and 4-hydroxynonenal (2). MDA is very reactive and reacts with nucleophilic amine groups such as lysine, arginine, and the amino termini of amino acids (3-5). It also reacts with any ketones or aldehydes from other sources, for example attached sugars or glycation products. Of particular importance is the bifunctional aldehydic property of MDA, which gives it the potential to cross-link proteins, thereby reducing their functional capacity.It is well established that the aorta stiffens with age, a process accelerated in diabetes, and a contributing factor is the glycation cross-linking of the structural framework of collagen (6, 7). The production of MDA from low density lipoprotein (LDL) provides another potential cross-linking agent. Physiologically, LDL insudates the arterial intima, and in developing atheroma, the LDL oxidation products and collagen are in intimate contact. We have therefore suggested that the LDLderived MDA may be responsible, at least in part, for the stiffening of the vascular system in aging, a process that is accelerated in diabetes mellitus, because of increased glycation of the collagen. The expected MDA cross-link after reduction based on previous reports is the imidopropene structure 1,3-di(N ⑀ -lysino) propane (see Fig. 1), bridging two lysines through the reaction with the aldehyde grou...

Increased aldehyde-modification of collagen type IV in symptomatic plaques – A possible cause of endothelial dysfunction

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Chronotoxicity of bromobenzene-induced hepatic injury in mice

“…In addition, we determined levels of MDA, an end product of lipid peroxidation. Since MDA can react with sulfhydryl groups, and has the potential to crosslink proteins (Esterbauer et al, 1991), it can reduce or abolish important protein functions (Slatter et al, 1999). Our present study demonstrated that BB-induced hepatic MDA levels in the ZT18 group were lower than those in the ZT6 group (third step in BB-induced hepatotoxicity), suggesting that the circadian mechanism that produces the difference in severity of BB-induced hepatotoxicity occurs within the first three steps of BB-induced hepatotoxicity.…”

Identification of a New Cross-link and Unique Histidine Adduct from Bovine Serum Albumin Incubated with Malondialdehyde

“…Previous studies employing acid hydrolysis did not reveal a cross-link involving a single MDA molecule under pseudo-physiological conditions in vitro (16). Here, we report some success in an attempt to isolate an MDA cross-link using alkaline hydrolysis of MDA reacted with both BSA and collagen.…”

“…When using radioactivity, the column fractions were counted using a LKB Wallac 1219 Rack Beta scintillation counter and radioactive peaks located in relation to standard amino acids as described earlier (16).…”