Inhibition of copper-mediated oxidation of LDL by rat serosal mast cells. A novel cellular protective mechanism involving proteolysis of the substrate under oxidative stress.
Rat serosal mast cells, when stimulated to exocytose their cytoplasmic granules, effectively blocked the copper-mediated oxidation of low density lipoproteins (LDLs) in vitro. This effect depended on the proteolytic activity of the formed extracellular granule remnants, since specific inhibition of chymase, the neutral protease that they contain, blocked the protective effect of the mast cells. The mechanism of this chymase-mediated inhibition of LDL oxidation was found to be binding of the copper ions present in the incubation medium by peptides released from LDL on proteolytic degradation of their apolipoprotein B (apoB) component. This was verified by demonstrating that addition of such peptides to LDL--copper ion mixtures completely prevented oxidation of LDL and that this protective effect could be overcome by adding copper ions in excess. Furthermore, proteolytic degradation of the apoB of LDL, with concomitant release of copper-containing peptides, left the partially degraded apoB without the copper ions necessary for propagation of LDL oxidation. These observations provide the first evidence for cell-mediated inhibition of LDL oxidation.
Lindstedt
K A
KA
Wihuri Research Institute, Helsinki, Finland.
Kokkonen
J O
JO
Kovanen
P T
PT
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D053818:Chymases; D003300:Copper / Q000378:metabolism / Q000494:pharmacology*; D003594:Cytoplasmic Granules / Q000378:metabolism; D005089:Exocytosis; D006493:Heparin / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010447:Peptide Hydrolases / Q000378:metabolism; D011509:Proteoglycans / Q000494:pharmacology; D051381:Rats; D012697:Serine Endopeptidases / Q000378:metabolism / Q000494:pharmacology; D012704:Serous Membrane / Q000166:cytology; D017392:Thiobarbituric Acid Reactive Substances
D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; D011509:Proteoglycans; D017392:Thiobarbituric Acid Reactive Substances; C036090:heparin proteoglycan; D003300:Copper; D006493:Heparin; D010447:Peptide Hydrolases; D012697:Serine Endopeptidases; D053818:Chymases