Hemin: a possible physiological mediator of low density lipoprotein oxidation and endothelial injury.
Oxidized low density lipoprotein (LDL), formed in vivo from presently unknown reactions, may play a role in atherogenesis. In vitro, transition metals such as iron and copper will facilitate LDL oxidation, but these metals are unlikely to exist in free form in normal body fluids. We have explored the possibility that LDL oxidation may be promoted by heme, a physiologically ubiquitous, hydrophobic, iron-containing compound. Indeed, during several-hour incubation, heme caused extensive oxidative modification of LDL; however, such modification requires only minutes in the presence of small amounts of H2O2 or preformed lipid hydroperoxides within the LDL. Oxidative interactions between heme, LDL, and peroxides lead to degradation of the heme ring and consequent release of heme iron, which further accelerates heme degradation. Coupled (evidently iron-catalyzed) heme degradation and LDL oxidation are both effectively inhibited by hydrophobic antioxidants and iron chelators. That such hemin-induced LDL oxidation may be involved in atherogenesis is supported by the finding that LDL oxidized by hemin is extremely cytotoxic to cultured aortic endothelial cells. Overall, these investigations not only lend support to the idea that LDL oxidation by physiological substances such as heme may play a role in the process of atherogenesis but also may have broader implications, as similar oxidative reactions between heme and unsaturated fatty acids may occur consequent to hemorrhagic injury.
Department of Medicine, University of Minnesota, Minneapolis 55455.
G
G
Balla
H S
HS
Jacob
J W
JW
Eaton
J D
JD
Belcher
G M
GM
Vercellotti
D002384:Catalysis; D002614:Chelating Agents / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000473:pathology*; D006427:Hemin / Q000502:physiology*; D006466:Hemopexin / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D010084:Oxidation-Reduction
D002614:Chelating Agents; D008077:Lipoproteins, LDL; D006427:Hemin; D006466:Hemopexin; D006861:Hydrogen Peroxide; D007501:Iron