Peroxynitrite releases copper from caeruloplasmin: implications for atherosclerosis

Abstract

Peroxynitrite may be formed in the vasculature by the reaction of superoxide with nitric oxide. When the blue copper-containing protein, caeruloplasmin, is incubated with peroxynitrite, copper is released, and ferroxidase activity and the blue colouration are lost. When plasma from normal subjects is incubated with peroxynitrite, the oxidant reacts with numerous plasma constituents but is still able to release copper from caeruloplasmin. As the ferroxidase activity of caeruloplasmin is lost in plasma in the presence of peroxynitrite, a second ferroxidase activity associated with peroxidised lipids, and not inhibited by azide, is formed.

Transition metal ions within human atherosclerotic lesions can catalyse the oxidation of low density lipoprotein by macrophages

“…As expected, Chelex-100 removed either copper or iron ions that had been added to Ham's F-10 medium and prevented them from catalysing LDL oxidation. These observations are supported by the work of Smith et al [17] and Swain and Gutteridge [18], who showed that gruel from atherosclerotic lesions contained significant levels of catalytically active copper and iron ions that were able to catalyse the oxidation of rat liver microsomes or linoleic acid micelles.…”

“…confirmed by Swain and Gutteridge [18], who also showed that lesions can contain ferrioxidase I activity, due to caeruloplasmin, and immunologically-detectable caeruloplasmin. Ferroxidase 3 activity, due to xanthine oxidase, was also present in some lesions.…”

“…We have shown that at acidic pH both caeruloplasmin [10] (the plasma coppercarrying protein) and transferrin [28] (the plasma iron-carrying protein) can generate catalytically active copper or iron that can oxidise LDL. It has also been shown that caeruloplasmin can oxidise LDL in phosphate buffered saline [29] and that peroxynitrite can make the copper in caeruloplasmin catalytically active so that it can catalyse lipid oxidation at pH 7.4 [30]. Furthermore, free radical attack on ferritin [31] or haem proteins [32,33] may release iron ions and in fact oxidised LDL has been shown to induce iron release from activated myoglobin [34].…”

“…Ferroxidase 3 activity, due to xanthine oxidase, was also present in some lesions. Homogenates of some lesions, but not all, could stimulate the oxidation of linoleic acid micelles in the presence of ascorbate [18]. In addition, catalytically active iron and copper have been shown to be present in mechanically disrupted early lesions and the normal arterial wall [19].…”

α‐Tocopherol mediated peroxidation in the copper (II) and met myoglobininduced oxidation of human low density lipoprotein: The influence of lipid hydroperoxides

“…The insertion of seeding 275 peroxides into the LDL particle could proceed through a reaction dependent upon 15-1ipoxygenase [40,41]. The relevance of copper dependent oxidation to atherosclerosis is also debatable but the recent finding of redox active transition metals in human atherosclerotic lesions and the peroxynitrite dependent release of copper from caeruloplasmin, the major extracellular copper containing protein, provide the evidence for its presence in lesions and a possible mechanism for its release [27,42]. However, it is important to note that tocopherol mediated peroxidation was only detectable in samples of LDL with low lipid hydroperoxide content and a high intrinsic resistance to oxidation (Fig.…”