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 th e LDL protein, apo B. We evaluated three possible mechanisms that may account for hemoglobin reactivity: oxidative activation by globin-diss ociated hemin following its transfer to LDL; peroxidase-like reactivit y 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 tra nsferred to LDL in the process of oxidation. The second mechanism was excluded because hemoglobin ferryl, unlike ferryl of horseradish perox idase, was not consumed in the process of LDL oxidation. Haptoglobin c ompletely inhibited cross-linking of globin in hemoglobin/H2O2 mixture s but not in myglobin/H2O2, as well as cross-linking of apo B and oxid ation of LDL lipids. Haptoglobin could not however abolish the hemoglo bin ferryl state, a finding that further supported exclusion of the se cond mechanism. We conclude that the active species in hemoglobin-indu ced LDL oxidation is the globin radical, as suggested in the third mec hanism. The present findings also show that haptoglobin functions as a major antioxidant thus protecting the vascular system.