Glucose-induced enhancement of hemin-catalyzed LDL oxidation in vitro and in vivo.
Growing evidence indicates that oxidative modification of low-density lipoprotein (LDL) is increased in diabetes mellitus; however, the mechanism(s) of this phenomenon is still unclear. gamma-Glutamyl semialdehyde (gammaGSA) is a product of hemin (Fe(3+)-protoporphyrin IX)-catalyzed oxidation of apolipoprotein B-100 (apoB- 100) proline and arginine residues. On reduction, gammaGSA forms 5-hydroxy-2-aminovaleric acid (HAVA). This report describes the application of sensitive HAVA assay, to characterize gammaGSA formation in LDL under normo- and hyperglycemic conditions, both in vitro and in vivo. In vitro studies revealed that apoB-100 proline and arginine residues are not oxidized to HAVA by HOCl or the myeloperoxidase/hydrogen peroxide (H(2)O(2)) oxidation system. Cu(2+), Cu(2+)/H(2)O(2), and Fe(2+) induced only minor HAVA formation. In contrast, the hemin oxidation system appeared reactive toward LDL apoB-100 proline and arginine residues. The resulting significant HAVA formation was specifically inhibited by a redox-inert ferric iron chelator. Glucose further enhanced hemin-induced increase in relative electrophoretic mobility of LDL and apoB-100 HAVAformation. In vivo we observed elevated concentrations of HAVA in LDL apoB-100 in patients with impaired glucose tolerance and with manifest diabetes mellitus. In conclusion, glucose promotes iron-mediated oxidation of apoB- 100 proline and arginine residues via a superoxide-dependent mechanism, thus rendering the LDL particles more atherogenic. The findings (a) identify a potential mechanism of enhanced atherogenesis in subjects with diabetes mellitus and (b) support the value of HAVA as a specific marker of LDL apoB-100 oxidation. Antioxid. Redox Signal. 7, 1507-1512.
Julius
U
U
Medical Clinic and Outpatient Department III, University Hospital Dresden, Dresden, Germany. julius@rcs.urz.tu-dresden.de
Pietzsch
J
J
D000328:Adult; D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000378:metabolism; D002384:Catalysis; D002417:Cattle; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006427:Hemin / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects
D000596:Amino Acids; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; C004387:2-amino-5-hydroxyvaleric acid; D006427:Hemin; D006861:Hydrogen Peroxide; D005947:Glucose