FIG. 2.

Potential pathways of MM-LDL formation in vivo. The physiological modification of LDL takes place by a variety of reactions, both enzymatic and nonenzymatic. The products of all these reactions can be rightfully designated as MM-LDL, although the oxidation may not be the primary event in many of these modifications. Lipid peroxidation is the primary reaction only in the lipoxygenase and free radical mediated pathways. Hydrolysis of SM by secretory SMase C may occur in acute phase response when the SMase level is increased in plasma (305) or by the putative SMase intrinsic to LDL (103). The hydrolysis of LDL SM to ceramide increases the oxidative susceptibility of LDL (271), and also results in the formation of aggregated LDL (249) that is superior to OxLDL in loading of macrophages with cholesterol. The action of sPLA2 on LDL produces an LPC-enriched LDL that should have strong chemotactic and pro-inflammatory effects. PAF acetylhydrolase (Lp-PLA₂) may be responsible for the hydrolysis of oxidatively truncated PC in LDL, releasing the cytotoxic aldehydes in addition to LPC. Desialylated LDL has been shown to be present in circulation (279), and is formed either by the action of sialidase or by free radical mediated reactions. This LDL was shown to promote foam cell formation. Glycation of LDL, which is more prevalent in diabetes (80), also increases foam cell formation, and increases the susceptibility of LDL to oxidation. The myeloperoxidase (MPO)-mediated oxidation of LDL results primarily in the modification of tyrosine residues of Apo B (97).