title: Human Hp1-1 and Hp2-2 phenotype-specific haptoglobin therapeutics are both effective in vitro and in guinea pigs to attenuate hemoglobin toxicity.
abstract: OBJECTIVE
  Infusion of purified haptoglobin (Hp) functions as an effective hemoglobin (Hb) scavenging therapeutic in animal models of hemolysis to prevent cardiovascular and renal injury. Epidemiologic studies demonstrate the phenotype heterogeneity of human Hp proteins and suggest differing vascular protective potential imparted by the dimeric Hp1-1 and the polymeric Hp2-2.
  
  
  RESULTS
  In vitro experiments and in vivo studies in guinea pigs were performed to evaluate phenotype-specific differences in Hp therapeutics. We found no differences between the two phenotypes in Hb binding and intravascular compartmentalization of Hb in vivo. Both Hp1-1 and Hp2-2 attenuate Hb-induced blood pressure response and renal iron deposition. These findings were consistent with equal prevention of Hb endothelial translocation. The modulation of oxidative Hb reactions by the two Hp phenotypes was not found to be different. Both phenotypes stabilize the ferryl (Fe(4+)) Hb transition state, provide heme retention within the complex, and prevent Hb-driven low-density lipoprotein (LDL) peroxidation. Hb-mediated peroxidation of LDL resulted in endothelial toxicity, which was equally blocked by the addition of Hp1-1 and Hp2-2.
  
  
  CONCLUSIONS
  The present data do not provide support for the concept that phenotype-specific Hp therapeutics offer differential efficacy in mitigating acute Hb toxicity.
authors: 1 Division of Internal Medicine, University of Zurich , Zurich, Switzerland .
authors: Miriam
authors: M
authors: Lipiski
authors: Jeremy W
authors: JW
authors: Deuel
authors: Jin Hyen
authors: JH
authors: Baek
authors: Wolfgang R
authors: WR
authors: Engelsberger
authors: Paul W
authors: PW
authors: Buehler
authors: Dominik J
authors: DJ
authors: Schaer
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D006242:Haptoglobins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006454:Hemoglobins / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male
chemical_list: D006242:Haptoglobins; D006454:Hemoglobins; D008077:Lipoproteins, LDL; D006861:Hydrogen Peroxide