title: Heme degradation and vascular injury.
abstract: Heme is an essential molecule in aerobic organisms. Heme consists of protoporphyrin IX and a ferrous (Fe(2+)) iron atom, which has high affinity for oxygen (O(2)). Hemoglobin, the major oxygen-carrying protein in blood, is the most abundant heme-protein in animals and humans. Hemoglobin consists of four globin subunits (alpha(2)beta(2)), with each subunit carrying a heme group. Ferrous (Fe(2+)) hemoglobin is easily oxidized in circulation to ferric (Fe(3+)) hemoglobin, which readily releases free hemin. Hemin is hydrophobic and intercalates into cell membranes. Hydrogen peroxide can split the heme ring and release "free" redox-active iron, which catalytically amplifies the production of reactive oxygen species. These oxidants can oxidize lipids, proteins, and DNA; activate cell-signaling pathways and oxidant-sensitive, proinflammatory transcription factors; alter protein expression; perturb membrane channels; and induce apoptosis and cell death. Heme-derived oxidants induce recruitment of leukocytes, platelets, and red blood cells to the vessel wall; oxidize low-density lipoproteins; and consume nitric oxide. Heme metabolism, extracellular and intracellular defenses against heme, and cellular cytoprotective adaptations are emphasized. Sickle cell disease, an archetypal example of hemolysis, heme-induced oxidative stress, and cytoprotective adaptation, is reviewed.
authors.affiliation: Department of Medicine, Division of Hematology, Oncology and Transplantation, Minneapolis, Minnesota 55455, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Belcher
authors.forename: Joan D
authors.initials: JD
authors.lastname: Beckman
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Balla
authors.forename: Jozsef
authors.initials: J
authors.lastname: Balla
authors.forename: Gregory
authors.initials: G
authors.lastname: Vercellotti
mesh_terms: D000755:Anemia, Sickle Cell / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000293:injuries; D004789:Enzyme Activation / Q000187:drug effects; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006427:Hemin / Q000378:metabolism / Q000494:pharmacology; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology
chemical_list: D006454:Hemoglobins; D016877:Oxidants; D006418:Heme; D006427:Hemin; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1
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