Oxidation of Low-Density Lipoprotein by Hemoglobin Stems from a Heme-Initiated Globin Radical:  Antioxidant Role of Haptoglobin

Abstract

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.

Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins

“…It has been suggested that globin-chain free radicals are available for localized amino acid oxidations (eg, within Hb) or radical transfer to non-Hb molecules (eg, lipoproteins). 9,10 The proposed final outcome of these reactions is Hb self-destruction, hemin loss, and globin chain cross-linking/ precipitation, which can ultimately lead to tissue damage. 11 It should be noted that the putative impact of these reactions on disease conditions is based on limited and indirect experimental evidence, so it remains uncertain whether significant quantities of Hb-Fe 4ϩ and radicals are generated during in vivo hemolysis and if they contribute to disease.…”

Methemoglobin—It's not just blue: A concise review

“…Endocytosis by macrophages results in lysosomal degradation of the protein and of the heme by heme oxygenase 1, releasing ferrous iron (Fe(II)), biliverdin, and CO [48]. Knock-out mice lacking Hp have no difficulty in clearing Hgb [49], rather the role of Hp would seem to be to protect against oxidative damage to lipids and LDL [50,51].…”

Monoamine-dependent Production of Reactive Oxygen Species Catalyzed by Pseudoperoxidase Activity of Human Hemoglobin

“…Hb has been known to have a weak peroxidase activity, since it degrades H2O2 in a peroxidase-like manner, 20) but it has no catalase-like activity. 6) Other hemoproteins have properties similar to Hb, and thus studies on various hemoproteins such as myoglobin (Mb) and horseradish peroxidase (HRP) provide us with general knowledge about the redox chemistry of hemes.…”