title: Haptoglobin Preserves Vascular Nitric Oxide Signaling during Hemolysis.
abstract: Hemolysis occurs not only in conditions such as sickle cell disease and malaria but also during transfusion of stored blood, extracorporeal circulation, and sepsis. Cell-free Hb depletes nitric oxide (NO) in the vasculature, causing vasoconstriction and eventually cardiovascular complications. We hypothesize that Hb-binding proteins may preserve vascular NO signaling during hemolysis.
  
  
  
  Characterization of an archetypical function by which Hb scavenger proteins could preserve NO signaling during hemolysis.
  
  
  
  We investigated NO reaction kinetics, effects on arterial NO signaling, and tissue distribution of cell-free Hb and its scavenger protein complexes.
  
  
  
  Extravascular translocation of cell-free Hb into interstitial spaces, including the vascular smooth muscle cell layer of rat and pig coronary arteries, promotes vascular NO resistance. This critical disease process is blocked by haptoglobin. Haptoglobin does not change NO dioxygenation rates of Hb; rather, the large size of the Hb:haptoglobin complex prevents Hb extravasation, which uncouples NO/Hb interaction and vasoconstriction. Size-selective compartmentalization of Hb functions as a substitute for red blood cells after hemolysis and preserves NO signaling in the vasculature. We found that evolutionarily and structurally unrelated Hb-binding proteins, such as PIT54 found in avian species, functionally converged with haptoglobin to protect NO signaling by sequestering cell-free Hb in large protein complexes.
  
  
  
  Sequential compartmentalization of Hb by erythrocytes and scavenger protein complexes is an archetypical mechanism, which may have supported coevolution of hemolysis and normal vascular function. Therapeutic supplementation of Hb scavengers may restore vascular NO signaling and attenuate disease complications in patients with hemolysis.
authors.affiliation: 1 Division of Internal Medicine.|2 Institute of Anesthesiology.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Schaer
authors.affiliation: 1 Division of Internal Medicine.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Deuel
authors.affiliation: 1 Division of Internal Medicine.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schildknecht
authors.affiliation: 1 Division of Internal Medicine.
authors.forename: Leila
authors.initials: L
authors.lastname: Mahmoudi
authors.affiliation: 3 Laboratory of Physical Chemistry and.|4 Centro Universitario de la Defensa, Carretera de Huesca, Zaragoza, Spain.
authors.forename: Ines
authors.initials: I
authors.lastname: Garcia-Rubio
authors.affiliation: 5 CSL Limited, Bio21 Institute, Parkville, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Owczarek
authors.affiliation: 6 Functional Genomics Center Zurich, and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schauer
authors.affiliation: 7 Institute of Inorganic Chemistry, ETH Zurich, Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kissner
authors.affiliation: 8 William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio.
authors.forename: Uddyalok
authors.initials: U
authors.lastname: Banerjee
authors.affiliation: 8 William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio.
authors.forename: Andre F
authors.initials: AF
authors.lastname: Palmer
authors.affiliation: 2 Institute of Anesthesiology.
authors.forename: Donat R
authors.initials: DR
authors.lastname: Spahn
authors.affiliation: 9 School of Medicine, University of Colorado Denver, Aurora, Colorado; and.
authors.forename: David C
authors.initials: DC
authors.lastname: Irwin
authors.affiliation: 1 Division of Internal Medicine.
authors.forename: Florence
authors.initials: F
authors.lastname: Vallelian
authors.affiliation: 9 School of Medicine, University of Colorado Denver, Aurora, Colorado; and.|10 Center of Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Buehler
authors.affiliation: 1 Division of Internal Medicine.|11 Institute of Evolutionary Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Dominik J
authors.initials: DJ
authors.lastname: Schaer
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D006242:Haptoglobins / Q000494:pharmacology*; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D006242:Haptoglobins; D009569:Nitric Oxide
keywords: PIT54; extravasation; haptoglobin; hemoglobin; hemolysis