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Haptoglobin halts hemoglobin’s havoc
Gregory J. Kato
Sickle Cell Vascular Disease Section, Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, and Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Address correspondence to: Gregory J. Kato, 10 Center Dr., MSC 1476, Building 10CRC, Room 5-5140, Bethesda, Maryland 20892-1476, USA. Phone: (301) 451-8497; Fax: (301) 451-7091; E-mail: gkato@nhlbi.nih.gov.
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Published July 20, 2009 - More info
J Clin Invest. 2009;119(8):2140–2142. https://doi.org/10.1172/JCI40258.
© 2009 The American Society for Clinical Investigation
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Abstract
Release of hemoglobin (Hb) into the circulation is a central pathophysiologic event that contributes to morbidity and mortality in chronic hemolytic anemias and severe malaria. These toxicities arise from Hb-mediated vasoactivity, possibly due to NO scavenging and localized tissue oxidative processes. Currently, there is no established treatment that targets circulating extracellular Hb. Here, we assessed the role of haptoglobin (Hp), the primary scavenger of Hb in the circulation, in limiting the toxicity of cell-free Hb infusion. Using a canine model, we found that glucocorticoid stimulation of endogenous Hp synthesis prevented Hb-induced hemodynamic responses. Furthermore, guinea pigs administered exogenous Hp displayed decreased Hb-induced hypertension and oxidative toxicity to extravascular environments, such as the proximal tubules of the kidney. The ability of Hp to both attenuate hypertensive responses during Hb exposure and prevent peroxidative toxicity in extravascular compartments was dependent on Hb-Hp complex formation, which likely acts through sequestration of Hb rather than modulation of its NO- and O2-binding characteristics. Our data therefore suggest that therapies involving supplementation of endogenous Hb scavengers may be able to treat complications of acute and chronic hemolysis, as well as counter the adverse effects associated with Hb-based oxygen therapeutics.
Authors
Felicitas S. Boretti, Paul W. Buehler, Felice D’Agnillo, Katharina Kluge, Tony Glaus, Omer I. Butt, Yiping Jia, Jeroen Goede, Claudia P. Pereira, Marco Maggiorini, Gabriele Schoedon, Abdu I. Alayash, Dominik J. Schaer
Hemoglobin (Hb) plays a critical role in vascular function — it carries oxygen and mediates adaptive vasodilation via NO signaling, most likely via nitrite reductase activity, under hypoxic conditions (1). When red blood cells lyse during intravascular hemolysis, Hb crosses the red blood cell membrane into plasma. Once decompartmentalized from red blood cells, free Hb potently induces oxidative stress and scavenges NO, reducing the bioavailability of this critical antioxidant and master regulator of vascular homeostasis, wreaking havoc on vascular health (2). In this issue of the JCI, Boretti et al. show, in canine and guinea pig models, that pharmacological activation of the glucocorticoid pathway induces expression of the Hb-scavenging protein haptoglobin (Hp), which sequesters cell-free plasma Hb and neutralizes much of its vasculotoxic oxidative stress, protecting against systemic hypertension and other vasculopathic outcomes (3).
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Hemolysis, NO scavenging, oxidative stress, and clinical outcomes
For decades, it has been known that Hb is a highly efficient scavenger of NO in vitro. However, only in recent years has it become more widely appreciated that cell-free Hb scavenges NO in vivo in human disease and produces clinical manifestations (Figure 1) (2). The depletion of NO, a crucial endogenous antioxidant, is compounded by the oxidative stress induced by decomposition of Hb into heme and elemental iron, highly oxidative co-conspirators against vascular health. Indeed, not only does a canine model of intravascular hemolysis acutely demonstrate the induction of systemic and pulmonary hypertension but also impaired creatinine clearance, presumably due to decreased renal blood flow (4). Overlapping syndromes have been observed in other human examples of acute hemoglobinemia (excess Hb in the blood plasma), such as the acute hemolytic transfusion reaction (abrupt hemolysis of transfused red blood cell), or following infusion of the first generation of cell-free blood substitutes (2). The acute experimental canine vasculopathy is partially reversed by administration of NO (4) or alternatively, as described in this issue by Boretti et al., by glucocorticoid-induced production of endogenous Hp (3).
Figure 1Model of pathologic and adaptive responses to intravascular hemolysis. A variety of disease conditions can give rise to intravascular hemolysis, including hemolytic anemias such as sickle-cell disease, thalassemia, hereditary spherocytosis, and red blood cell enzymopathies and, to a less-appreciated extent, infection, inflammation, and diabetes mellitus. Extracellular Hb produces a set of pathological effects. It is oxidized to methemoglobin (MetHb) as it scavenges NO directly, depleting this endogenous vasodilator, antioxidant, and master regulator of vascular health. In addition, Hb releases heme and elemental iron (Fe), both of which are intensely oxidative. The net result of extracellular Hb release is oxidative stress, vasoconstriction, and vasculopathy. Glucocorticoids can increase the expression of CD163 and CD91 and, as shown in the study in this issue of the JCI by Boretti et al. (3), also Hp, potentially by either physiologic or pharmacologic stimulation. Hp avidly binds extracellular Hb and suppresses its oxidative consequences, as demonstrated by Boretti et al., largely by preventing its extravasation from the blood vessel lumen to the extraluminal interstitial space, in which some of these oxidative events appear to occur. Hp escorts Hb to the CD163 scavenger receptor on reticuloendothelial macrophages. These cells internalize the receptor-Hp-Hb complex, with consequent induction of heme oxygenase–1 and IL-10, providing antioxidant and antiinflammatory effects. CD163 also is capable, to some extent, of binding free Hb directly. Another adaptive protein, hemopexin, binds free heme and carries it to the macrophage receptor CD91, which also induces heme oxygenase–1. Transferrin transports non-heme iron in plasma, protecting against irons’s oxidative properties.
Sickle-cell disease has provided the most well-documented example of chronic hemolysis and clinical vasculopathy, with markers of hemolysis-induced NO scavenging statistically linked with pulmonary hypertension, leg ulceration, priapism, and cerebrovascular disease (5). Reports also have begun to accumulate for these same exact complications, arising in other non-sickling, acute, and chronic hemolytic disorders, supporting a contributory role for hemolysis in the pathophysiology of this vasculopathy syndrome (5). This growing list includes thalassemia, autoimmune hemolytic anemia, malaria, paroxysmal nocturnal hemoglobinuria, unstable hemoglobinopathy, and hereditary membranopathies (5).
The biological importance of these pathways is emphasized by the redundant and overlapping mechanisms that have evolved to detoxify cell-free plasma Hb. First among these is Hp, a tetrameric plasma glycoprotein that binds cell-free plasma Hb and quickly escorts it to the CD163 protein, in which the Hp-Hb complex is avidly bound and cleared from plasma, depleting plasma Hp in the process (6) (Figure 1). Boretti et al. (3) found that Hp binding to Hb is sufficient to prevent the generation of oxidant species from cell-free Hb that would otherwise mediate hypertension and other adverse vascular outcomes, perhaps in part by sequestering Hb in a high-molecular-weight complex that would not extravasate into the subendothelial space. Interestingly, Boretti et al. also show that Hp-bound Hb has a very high oxygen affinity, which should correspond to increased nitrite reductase activity (1), potentially stimulating the activity of Hp-Hb complexes to produce the endogenous antioxidant NO from nitrite. As part of the teleological evidence of the biological influence of cell-free plasma Hb, additional Hb-binding pathways have evolved, including sequestration of Hb in HDL particles by Hp-related protein and the ability of CD163 scavenger receptor–1 to bind free Hb to some extent, even after Hp has been depleted (7). In addition, the heme-binding protein hemopexin has evolved to mop up the toxic porphyrin heme ring released from decomposing cell-free Hb, and heme-metabolizing enzymes, such as heme oxygenase–1, provide a functional antioxidant effect that is protective to vascular health (8, 9) (Figure 1). Finally, plasma transferrin protein sequesters and safely transports elemental iron released from the heme ring, one of the most oxidative substances in the human body.
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