Oxidation of low-density lipoprotein by hemoglobin stems from a heme-initiated globin radical: antioxidant role of haptoglobin.
Hemoglobin, known as a poor peroxidase, has been recently found to be a highly reactive catalyzer of low-density lipoprotein (LDL) oxidation resulting in oxidation of LDL lipids and covalent cross-linking of the LDL protein, apo B. We evaluated three possible mechanisms that may account for hemoglobin reactivity: oxidative activation by globin-dissociated hemin following its transfer to LDL; peroxidase-like reactivity of the ferryl iron active state in intact hemoglobin; and oxidation by a globin radical formed in oxidized hemoglobin. The first mechanism was ruled out because only a minor fraction of hemin was actually transferred to LDL in the process of oxidation. The second mechanism was excluded because hemoglobin ferryl, unlike ferryl of horseradish peroxidase, was not consumed in the process of LDL oxidation. Haptoglobin completely inhibited cross-linking of globin in hemoglobin/H2O2 mixtures but not in myglobin/H2O2, as well as cross-linking of apo B and oxidation of LDL lipids. Haptoglobin could not however abolish the hemoglobin ferryl state, a finding that further supported exclusion of the second mechanism. We conclude that the active species in hemoglobin-induced LDL oxidation is the globin radical, as suggested in the third mechanism. The present findings also show that haptoglobin functions as a major antioxidant thus protecting the vascular system.
Miller
Y I
YI
The Sackler Institute of Molecular Medicine, Sackler Faculty of Medicine, Tel Aviv University, Israel.
Altamentova
S M
SM
Shaklai
N
N
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002417:Cattle; D003300:Copper / Q000494:pharmacology; D003432:Cross-Linking Reagents; D005914:Globins / Q000737:chemistry / Q000378:metabolism*; D006139:Guaiacol / Q000378:metabolism; D006242:Haptoglobins / Q000502:physiology*; D006418:Heme / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D006454:Hemoglobins / Q000378:metabolism* / Q000494:pharmacology; D006735:Horseradish Peroxidase / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000502:physiology; D009211:Myoglobin / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects
D000975:Antioxidants; D003432:Cross-Linking Reagents; D006242:Haptoglobins; D006454:Hemoglobins; D008077:Lipoproteins, LDL; D009211:Myoglobin; D006418:Heme; D006139:Guaiacol; D006427:Hemin; D003300:Copper; D005914:Globins; D006861:Hydrogen Peroxide; D007501:Iron; D006735:Horseradish Peroxidase