Elevated levels of protein-bound p-hydroxyphenylacetaldehyde, an amino-acid-derived aldehyde generated by myeloperoxidase, are present in human fattystreaks, intermediate lesions and advanced atherosclerotic lesions

Reactive aldehydes might have a pivotal role in the pathogenesis of atheros clerosis by covalently modifying low-density lipoprotein (LDL). However, th e identities of the aldehyde adducts that form on LDL in vivo are not yet c learly established. We previously demonstrated that the haem protein myelop eroxidase oxidizes proteins in the human artery wall, We also have shown th at p-hydroxyphenylacetaldehyde (pHA), the aldehyde that forms when myeloper oxidase oxidizes L-tyrosine, covalently modifies the N-epsilon-lysine resid ues of proteins. The resulting Schiff base can be quantified as N-epsilon-[ 2-(p-hydroxyphenyl)ethyl]lysine (pHA-lysine) after reduction with NaCNBH3. Here we demonstrate that pHA-lysine is a marker for LDL that has been modif ied by myeloperoxidase, and that water-soluble, but not lipid-soluble, anti oxidants inhibit the modification of LDL protein. To determine whether myel operoxidase-generated aldehydes might modify LDL in vivo, we used a combina tion of isotope-dilution GC-MS to quantify pHA-lysine in aortic tissues at various stages of lesion evolution, We also analysed LDL isolated from athe rosclerotic aortic tissue, Comparison of normal and atherosclerotic aortic tissue demonstrated a significant elevation (more than 10-fold) of the redu ced Schiff base adduct in fatty streaks, intermediate lesions and advanced lesions compared with normal aortic tissue. Moreover, the level of pHA-lysi ne in LDL recovered from atherosclerotic aortic intima was 200-fold that in plasma LDL of healthy donors. These results indicate that pHA-lysine, a sp ecific covalent modification of LDL, is generated in human atherosclerotic vascular tissue. They also raise the possibility that reactive aldehydes ge nerated by myeloperoxidase have a role in converting LDL into an atherogeni c lipoprotein.