Ceruloplasmin and cardiovascular disease

Transition metal ion-mediated oxidation is a commonly used model system for studies of the chemical, structural, and functional modifications of low-d ensity lipoprotein (LDL). The physiological relevance of studies using free metal ions is unclear and has led to an exploration of free metal ion-inde pendent mechanisms of oxidation. We and others have investigated the role o f human ceruloplasmin (Cp) in oxidative processes because it the principal copper-containing protein in serum. There is an abundance of epidemiologica l data that suggests that serum Cp may be an important risk factor predicti ng myocardial infarction and cardiovascular disease. Biochemical studies ha ve shown that Cp is a potent catalyst of LDL oxidation in vitro. The pro-ox idant activity of Cp requires an intact structure, and a single copper atom at the surface of the protein, near His(426), is required for LDL oxidatio n. Under conditions where inhibitory protein (such as albumin) is present, LDL oxidation by Cp is optimal in the presence of superoxide, which reduces the surface copper atom of Cp. Cultured vascular endothelial and smooth mu scle cells also oxidize LDL in the presence of Cp. Superoxide release by th ese cells is a critical factor regulating the rate of oxidation. Cultured m onocytic cells, when activated by zymosan, can oxidize LDL, but these cells are unique in their secretion of Cp. Inhibitor studies using Cp-specific a ntibodies and antisense oligonucleotides show that Cp is a major contributo r to LDL oxidation by these cells. The role of Cp in lipoprotein oxidation and atherosclerotic lesion progression in vivo has not been directly assess ed and is an important area for future studies. (C) 2000 Elsevier Science I nc.