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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2225-2226. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Weiss, M. J. Search for Related Content PubMed Articles by Weiss, M. J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Comment on Hvidberg et al, page 2572 Handling heme Mitchell J. Weiss THE CHILDREN'S HOSPITAL OF PHILADELPHIA Hemopexin is a plasma protein that binds heme with high affinity. Hvidberg and colleagues report here that hemopexin-heme is cleared from the circulation by the low-density lipoprotein receptor-related protein (LRP)/CD91, a multifunctional scavenger. This helps to define a biologically important pathway for eliminating potentially toxic-free heme. As a prosthetic group bound to various proteins, the small molecule heme has big functions, including oxygen binding, electron transport, catalysis, and intracellular signaling.1 In contrast, free heme is a potent oxidant causing cytotoxicity and inflammation. Circulating heme released from proteins after cell breakdown is linked to various disorders including atherosclerosis, renal injury, and central nervous system (CNS) damage.2 This is particularly important in hemorrhage and hemolysis (both acute and chronic) because erythrocyte hemoglobin is an abundant heme source. Haptoglobin and hemopexin bind hemoglobin and heme, respectively, to limit their reactivities and facilitate their catabolism via receptor-mediated endocytosis. In 2001, Kristiansen and colleagues identified the monocyte/macrophage protein CD163 as a scavenger receptor for hemoglobin-haptoglobin. Now, the same group demonstrates that hemopexin-heme is removed from circulation by the low-density lipoprotein (LDL) receptor-related protein (LRP/CD91), a multifunctional scavenger expressed in brain, placenta, liver, and macrophage/monocytes. Together, these studies define an important set of pathways that protect against noxious free heme (see figure) and identify new areas of investigation for heme biology. By virtue of its restricted expression pattern, LRP/CD91 is predicted to deliver hemopexin-heme into specific tissues. This has potential biological consequences. LRP/CD91 transports its cargo to lysosomes where hemopexin is degraded, presumably releasing intact heme. Inside cells, heme regulates gene expression by modulating the DNA binding activity and subcellular localization of transcription factors.3 One consequence is induction of heme oxygenase-1 (HO-1), which degrades heme into metabolites with potent antioxidant and anti-inflammatory activities.4 The current study found that hemopexinheme taken up by LRP/CD91 induces HO-1 in monocytes, which could inhibit their inflammatory functions. Heme recruitment by LRP/CD91 could induce HO-1 and its beneficial effects in other tissues as well. The CNS is of interest because free heme is implicated in the pathogenesis of both chronic neurodegenerative disorders and acute tissue damage after intracranial hemorrhage.5 Moreover, hemopexin is abundant in cerebrospinal fluid, and LRP/CD91 is expressed in neurons. Hence, heme uptake by LRP/CD91 could protect neurons by inducing HO-1. Another issue is whether heme brought into cells by LRP/CD91 could remain intact and be recycled directly into proteins, for example, in hepatocytes, where LRP is expressed and protein heme requirements are relatively high. View larger version (26K): [in this window] [in a new window]   Overview of the receptor pathways for endocytosis of extracellular heme and hemoglobin in complex with hemopexin and haptoglobin, respectively. See the complete figure in the article beginning on page 2572.   LRP/CD91 is a transmembrane protein with numerous functions, including plasma protein scavenging, intracellular signaling, and neurotransmission. Hemopexin-heme binding could affect these functions, particularly in pathological states that saturate the receptor. For example, LRP/CD91 removes plasma proteases and cofactors involved in blood coagulation. Modulation of LRP function by high levels of hemopexin-heme may influence this process to impact clot formation or dissolution. In principle, this mechanism could contribute to thrombophilia associated with many hemolytic disorders.6 Finally, genetic variations in heme uptake pathways could contribute to common multifactorial diseases. Polymorphisms in haptoglobin affect vascular complications in diabetics, probably due to functional differences in neutralizing the oxidative effects of globin-associated heme.7 It is also possible that genetic variations in heme metabolism by the newly defined hemopexin-heme-LRP/CD91 pathway affect susceptibility to vascular and nervous system disorders that are perpetuated by oxidative injury. References Ponka P. Cell biology of heme. Am J Med Sci. 1999;318: 241-256.[CrossRef][Medline] [Order article via Infotrieve] Kumar S, Bandyopadhyay U. Free heme toxicity and its detoxification systems in human. Toxicol Lett. 2005;157: 175-188.[CrossRef][Medline] [Order article via Infotrieve] Suzuki H, Tashiro S, Hira S, et al. Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1. EMBO J. 2004;23: 2544-2553.[CrossRef][Medline] [Order article via Infotrieve] Otterbein LE, Soares MP, Yamashita K, Bach FH. Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol. 2003;24: 449-455.[CrossRef][Medline] [Order article via Infotrieve] Takeda A, Itoyama Y, Kimpara T, et al. Heme catabolism and heme oxygenase in neurodegenerative disease. Antioxid Redox Signal. 2004;6: 888-894.[Medline] [Order article via Infotrieve] Eldor A, Rachmilewitz EA. The hypercoagulable state in thalassemia. Blood. 2002;99: 36-43.[Abstract/Free Full Text] Melamed-Frank M, Lache O, Enav BI, et al. Structure-function analysis of the antioxidant properties of haptoglobin. Blood. 2001;98: 3693-3698.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Identification of the receptor scavenging hemopexin-heme complexes Vibeke Hvidberg, Maciej B. Maniecki, Christian Jacobsen, Peter Højrup, Holger J. Møller, and Søren K. Moestrup Blood 2005 106: 2572-2579. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Weiss, M. J. Search for Related Content PubMed Articles by Weiss, M. J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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