Abstract
Oxidation of low density lipoprotein (LDL) results in changes to the lipoprotein that are potentially atherogenic. Numerous studies have shown that macrophages cultured in vitro can promote LDL oxidation via a transition metal-dependent process, yet the exact mechanisms that are responsible for macrophage-mediated LDL oxidation are not understood. One contributing mechanism may be the ability of macrophages to reduce transition metals. Reduced metals (such as Fe(II) or Cu(I)) rapidly react with lipid hydroperoxides, leading to the formation of reactive lipid radicals and conversion of the reduced metal to its oxidized form. We demonstrate here the ability of macrophages to reduce extracellular iron and copper and identify a contributing mechanism. Evidence is provided that a proportion of cell-mediated metal reduction is due to direct trans-plasma membrane electron transport. Glucagon suppressed both macrophage-mediated metal reduction and LDL oxidation. Although metal reduction was augmented when cells were provided with a substrate for thiol production, thiol export was not a strict requirement for cell-mediated metal reduction. Similarly, while the metal-dependent acceleration of LDL oxidation by macrophages was augmented by thiol production, macrophages could still promote LDL oxidation when thiol export was minimized (by substrate limitation). This study identifies a novel mechanism that may contribute to macrophage-mediated LDL oxidation and may also reveal potential new strategies for the inhibition of this process.
Highlights
The oxidative modification of LDL1 results in numerous changes to the lipoprotein that are potentially atherogenic [1, 2]
Macrophage-mediated low density lipoprotein (LDL) Oxidation and Antioxidation and Influence of Transition Metals and Cystine—To examine the role of transition metals in cell-mediated LDL oxidation, LDL oxidation was assessed in a simple buffered salt solution (HBSS) by measurement of the consumption of polyunsaturated cholesteryl esters and of ␣-tocopherol and the generation of cholesteryl ester hydroperoxides (Fig. 1)
When Hanks’ balanced salt solution (HBSS) was supplemented with 3 M iron and 0.01 M copper (equal to their concentrations in Ham’s F-10 medium, which is permissive for cell-mediated LDL oxidation [8]), monocyte-derived macrophages (MDM) produced a greater degree of LDL oxidation than in equivalent cell-free incubations
Summary
The oxidative modification of LDL1 results in numerous changes to the lipoprotein that are potentially atherogenic [1, 2]. There is evidence for the presence of transition metals in plaque [16, 17], and it is known that physiologically relevant forms of both iron (e.g. hemin and ferritin) and copper (e.g. ceruloplasmin) can promote LDL oxidation in vitro, under conditions related to inflammation [17,18,19]. These studies indicate (but do not prove) that metal-catalyzed LDL oxidation could be one contributing factor in the generation of oxidized LDL during atherosclerosis. Our hypothesis was that macrophages’ ability to promote LDL oxidation is related to their ability to reduce transition metals and that a direct macrophage plasma membrane electron transport system may account for a significant proportion of macrophagemediated metal reduction
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
