Haptoglobin phenotypes differ in their ability to inhibit heme transfer from hemoglobin to LDL.
LDL oxidation plays a pivotal role in atherosclerosis. Excellular hemoglobin (Hb) is a trigger of LDL oxidation. By virtue of its ability to bind hemoglobin, haptoglobin (Hp) serves as an antioxidant. Oxidation of LDL by hemoglobin was analyzed to occur by heme displacement from methemoglobin lodged in LDL. The LDL-associated heme is disintegrated, and iron inserted this way in LDL triggers formation of lipid peroxides. The genetic polymorphism of haptoglobin was found to be a risk factor in the pathogenesis of atherosclerosis. Individuals with Hp2-2 have more vascular incidences as compared to those with Hp1-1. In the current study, oxidation of LDL by metHb was carried out at physiological pH without addition of external peroxides. Hb-derived oxidation of lipids and protein was found to be practically inhibited by Hp1-1 but only partially by Hp2-2. Heme transfer from metHb to LDL was almost completely omitted by Hp1-1 and only partially by Hp2-2. We concluded that partial heme transfer from the Hb-Hp2-2 complex to LDL is the reason for oxidation of LDL lipids as well as protein. These findings provide a molecular basis for Hp2-2 atherogenic properties.
Bamm
Vladimir V
VV
Department of Human Genetics and Molecular Medicine, Sackler Institute of Molecular Medicine, Tel Aviv University, 69978 Tel-Aviv, Israel.
Tsemakhovich
Vladimir A
VA
Shaklai
Matityahu
M
Shaklai
Nurith
N
D000466:Alkadienes / Q000737:chemistry; D000483:Alleles; D000975:Antioxidants / Q000737:chemistry; D001692:Biological Transport; D006242:Haptoglobins / Q000737:chemistry* / Q000235:genetics*; D006418:Heme / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006454:Hemoglobins / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008706:Methemoglobin / Q000737:chemistry; D010084:Oxidation-Reduction; D010641:Phenotype; D013056:Spectrophotometry, Ultraviolet; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry
D000466:Alkadienes; D000975:Antioxidants; D006242:Haptoglobins; D006454:Hemoglobins; D008077:Lipoproteins, LDL; D014443:Tyrosine; D006418:Heme; D008706:Methemoglobin; C007543:dityrosine