Dataset Information

Human Hp1-1 and Hp2-2 phenotype-specific haptoglobin therapeutics are both effective in vitro and in guinea pigs to attenuate hemoglobin toxicity.

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.

SUBMITTER: Lipiski M

PROVIDER: S-EPMC3809386 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Publications

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 M Deuel Jeremy W JW Baek Jin Hyen JH Engelsberger Wolfgang R WR Buehler Paul W PW Schaer Dominik J DJ

Antioxidants & redox signaling 20130328 14

<h4>Aims</h4>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.<h4>Results</h4>In vitro experiments and in vivo studies in guinea pigs were performed to evaluate phenotype-specific dif ...[more]

PMID: 23418677

Similar Datasets

Project description:BACKGROUND:Preclinical studies have evaluated haptoglobin (Hp) polymers from pooled human plasma as a therapeutic protein to attenuate toxic effects of cell-free hemoglobin (Hb). Proof of concept studies have demonstrated efficacy of Hp in hemolysis associated with transfusion and sickle cell anemia. However, phenotype-specific Hp products might be desirable to exploit phenotype specific activities of Hp 1-1 versus Hp 2-2, offering opportunities for recombinant therapeutics. Prohaptoglobin (proHp) is the primary translation product of the Hp mRNA. ProHp is proteolytically cleaved by complement C1r subcomponent-like protein (C1r-LP) in the endoplasmic reticulum. Two main allelic Hp variants, HP1 and HP2 exist. The larger HP2 is considered to be the ancestor variant of all human Hp alleles and is characterized by an ?2-chain, which contains an extra cysteine residue that pairs with additional ?-chains generating multimers with molecular weights of 200-900 kDa. The two human HP1 alleles (HP1F and HP1S) differ by a two-amino-acid substitution polymorphism within the ?-chain and are derived from HP2 by recurring exon deletions. RESULTS:In the present study, we describe a process for the production of recombinant phenotype specific Hp polymers in mammalian FS293F cells. This approach demonstrates that efficient expression of mature and fully functional protein products requires co-expression of active C1r-LP. The functional characterization of our proteins, which included monomer/polymer distribution, binding affinities as well as NO-sparing and antioxidant functions, demonstrated that C1r-LP-processed recombinant Hp demonstrates equal protective functions as plasma derived Hp in vitro as well as in animal studies. CONCLUSIONS:We present a recombinant production process for fully functional phenotype-specific Hp therapeutics. The proposed process could accelerate the development of Hb scavengers to treat patients with cell-free Hb associated disease states, such as sickle cell disease and other hemolytic conditions.

Dataset Information

Human Hp1-1 and Hp2-2 phenotype-specific haptoglobin therapeutics are both effective in vitro and in guinea pigs to attenuate hemoglobin toxicity.

Aims

Results

Innovation and conclusion

Publications

Human Hp1-1 and Hp2-2 phenotype-specific haptoglobin therapeutics are both effective in vitro and in guinea pigs to attenuate hemoglobin toxicity.

Similar Datasets

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