Acidic pH enables caeruloplasmin to catalyse the modification of low‐density lipoprotein

Abstract

LDL oxidation within the arterial wall may contribute to the disease of atherosclerosis. There is some evidence that elevated plasma levels of copper are associated with an increased risk of coronary artery disease. We have investigated the conditions under which caeruloplasmin (the plasma copper carrier protein) can catalyse the macrophage-mediated modification of LDL. LOW concentrations of C&O, (< 1 PM) could catalyse the macrophagemediated modification of LDL. Native caeruloplasmin was unable to catalyse the modification of LDL at pH 7.4, but could do so after preincubation at acidic pH. After preincubation at acidic pH, concentrations of caeruloplasmin as low as 30 pg/ml (about one-tenth of the human plasma level) could catalyse significant LDL oxidation when added to macrophages. The activation of copper in caeruloplasmin in atherosclerotic lesions due to a localised acidic pH may help to explain why LDL oxidation occurs in these areas of the body.

Mechanism of the antioxidant to pro-oxidant switch in the behavior of dehydroascorbate during LDL oxidation by copper(II) ions

“…Caeruloplasmin, which contains most of the plasma copper, has also been shown to oxidise LDL by cells in vitro [13][14][15], which depends on superoxide generated by these cells [15]. The presence in human atherosclerotic lesions of redox-active metal ions [16] and products indicative of freeradical attack upon proteins [17,18] is consistent with oxidation catalyzed by metal ions.…”

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

“…There is circumstantial evidence to suggest that the interior of atherosclerotic lesions may be acidic (discussed in [27]). 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].…”

“…It has been demonstrated in vitro, however, that LDL can be oxidised by the main cells present in atherosclerotic lesions, namely endothelial cells [3], smooth muscle cells [4], monocyte-macrophages [5 7] and lymphocytes [8]. Most workers find that LDL oxidation by cells requires the presence of transition metal ions, usually iron [7,9], but copper ions will also catalyse the oxidation [9,10]. A sufficiently high concentration of iron [7,9] or copper [10,11] can catalyse the oxidation of LDL in the absence of cells.…”

“…Most workers find that LDL oxidation by cells requires the presence of transition metal ions, usually iron [7,9], but copper ions will also catalyse the oxidation [9,10]. A sufficiently high concentration of iron [7,9] or copper [10,11] can catalyse the oxidation of LDL in the absence of cells.…”

Iron released from transferrin at acidic pH can catalyse the oxidation of low density lipoprotein

“…It is possible that low local pN values within the arterial wall may release iron from transferrin (or copper from caeruioplasmin [22]) which may catalyse this oxidation of LDL.…”