Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs

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 Hbinduced 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 O 2 -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.

Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins

“…29 When bound within the large molecular size Hb:Hp complex (Ͼ 150 kDa), Hb remains sequestered within the intravascular space and its translocation into the kidney and across the endothelial layer appears to be prevented. This simple mechanism keeps potentially adverse biochemical reactions of the free Hb with NO and/or peroxides away from the most susceptible anatomic sites such as the vascular wall.…”

Proteomics Analysis of Porcine Serum Proteins by LC-MS/MS after Foot-and-Mouth Disease Virus (FMDV) Infection

“…Haptoglobin possesses antioxidant activity towards hemoglobin-stimulated lipid peroxidation and halts hemoglobin's havoc as well [13]. According to the study of Boretti et al [6], haptoglobin induction might occur as part of the glucocorticoid-induced compensatory response to inflammation, in addition to induction of CD163 and CD91 [15]. Haptoglobin is a major bovine acute phase protein, and it has been evaluated as a marker of primary replication of FMDV in 12 naturally infected cattle [10].…”

Cell-Free Hemoglobin and Its Scavenger Proteins: New Disease Models Leading the Way to Targeted Therapies

“…The pathophysiologic response to Hb and its consumption of NO is observed primarily as an increase in systolic/diastolic and mean arterial blood pressure (MAP) with cardiac output either unchanged ) or decreased (Minneci et al 2005). This consistently causes an increase in systemic vascular resistance, or vasoconstriction (Reiter et al 2002;Minneci et al 2005;Boretti et al 2009). In addition, heart rate and stroke volume are often deceased with the aggregate hemodynamic response resulting in decreased perfusion to some organ systems, particularly the kidneys.…”