A considerable body of evidence implicates reactive aldehydes in vascular damage. Such aldehydes are produced during lipid peroxidation of low density lipoprotein (LDL), for example, and they may mediate many of the atherogenic effects of oxidized LDL. The open-chain form of glucose also is a reactive aldehyde and, at concentrations that prevail in diabetes, it may promote vascular disease by covalently modifying lipoproteins and artery wall proteins. The investigators have recently discovered another biological pathway for generating reactive aldehyde. It involves myeloperoxidase, a heme protein secreted by phagocytes. The enzyme uses hydrogen peroxide generated by phagocytes to make hypochlorous acid (HOCI), which converts free amino acids to their respective aldehydes. For example, HOCI oxidizes serine to glycolaldehyde, which cross-links proteins and also forms an advanced glycation end product (AGE). It converts threonine into acrolein, an extremely reactive alkylating and cytotoxic agent. Such aldehydes may covalently modify LDL, rendering it atherogenic, or they may contribute to artery wall damage by forming adducts with proteins, lipids and DNA. Thus, reactive aldehydes derived from lipid peroxidation, reducing sugars and amino acid oxidation may be of central importance in the genesis of vascular disease. The overall goal of this proposal is to test the hypothesis that activated phagocytes are a major source of reactive aldehydes and AGEs in atherosclerosis and at sites of inflammation. We plan to determine whether phagocyte-generated al react with proteins in vitro to form novel covalent adducts and AGEs. Parallel studies will establish whether reactive alde and AGEs derived through amino acid oxidation are present in human inflammatory tissue. Genetically altered animal models will be used to determine which pathways generate reactive aldehydes and AGEs in vivo. Finally, the investigators will determine whether macrophages possess a novel receptor for aldehyde-modified lipoproteins that might contribute to the deposition of cholesterol in the artery wall.
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