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Human hp1-1 and hp2-2 phenotype-specific haptoglobin therapeutics are both effective in vitro and in Guinea pigs to attenuate hemoglobin toxicity


Lipiski, Miriam; Deuel, Jeremy W; Baek, Jin Hyen; Engelsberger, Wolfgang R; Buehler, Paul W; Schaer, Dominik J (2013). Human hp1-1 and hp2-2 phenotype-specific haptoglobin therapeutics are both effective in vitro and in Guinea pigs to attenuate hemoglobin toxicity. Antioxidants & Redox Signaling, 19(14):1619-1633.

Abstract

Aims: 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. Innovation and Conclusion: The present data do not provide support for the concept that phenotype-specific Hp therapeutics offer differential efficacy in mitigating acute Hb toxicity. Antioxid. Redox Signal. 19, 1619-1633.

Aims: 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. Innovation and Conclusion: The present data do not provide support for the concept that phenotype-specific Hp therapeutics offer differential efficacy in mitigating acute Hb toxicity. Antioxid. Redox Signal. 19, 1619-1633.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic and Policlinic for Internal Medicine
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2013
Deposited On:07 Nov 2013 13:55
Last Modified:05 Apr 2016 17:07
Publisher:Mary Ann Liebert
ISSN:1523-0864
Publisher DOI:https://doi.org/10.1089/ars.2012.5089
PubMed ID:23418677
Permanent URL: https://doi.org/10.5167/uzh-84415

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