A novel hemoglobin-binding peptide reduces cell-free hemoglobin in murine hemolytic anemia
| Autor: | Neil Hogg, Sandra L. Holzhauer, Timothy C. Flewelen, Dawn Retherford, Kirkwood A. Pritchard, Cheryl A. Hillery, Hao Xu, Anne C. Frei, Nancy J. Wandersee, Deron W. Jones, Madelyn S. Hanson |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Hemolytic anemia
Hemoglobin binding Anemia Hemolytic Physiology Anemia Vasodilator Agents Spherocytosis Mice Transgenic Anemia Sickle Cell Spherocytosis Hereditary Biology Nitric Oxide Hemolysis Hereditary spherocytosis chemistry.chemical_compound Hemoglobins Mice Integrative Cardiovascular Physiology and Pathophysiology Apolipoproteins E Physiology (medical) medicine Animals Humans Heme medicine.disease Molecular biology Endocytosis Peptide Fragments Phenylhydrazines Mice Inbred C57BL Vasodilation Disease Models Animal Protein Transport Biochemistry chemistry Liver Acute Disease Chronic Disease Hemoglobin Cardiology and Cardiovascular Medicine Peptides Half-Life Protein Binding |
| Popis: | Hemolysis can saturate the hemoglobin (Hb)/heme scavenging system, resulting in increased circulating cell-free Hb (CF-Hb) in hereditary and acquired hemolytic disease. While recent studies have suggested a central role for intravascular hemolysis and CF-Hb in the development of vascular dysfunction, this concept has stimulated considerable debate. This highlights the importance of determining the contribution of CF-Hb to vascular complications associated with hemolysis. Therefore, a novel Hb-binding peptide was synthesized and linked to a small fragment of apolipoprotein E (amino acids 141–150) to facilitate endocytic clearance. Plasma clearance of hE-Hb-b10 displayed a rapid phase t1/2of 16 min and slow phase t1/2of 10 h, trafficking primarily through the liver. Peptide hE-Hb-B10 decreased CF-Hb in mice treated with phenylhydrazine, a model of acute hemolysis. Administration of hE-Hb-B10 also attenuated CF-Hb in two models of chronic hemolysis: Berkeley sickle cell disease (SS) mice and mice with severe hereditary spherocytosis (HS). The hemolytic rate was unaltered in either chronic hemolysis model, supporting the conclusion that hE-Hb-B10 promotes CF-Hb clearance without affecting erythrocyte lysis. Interestingly, hE-Hb-B10 also decreased plasma ALT activity in SS and HS mice. Although acetylcholine-mediated facialis artery vasodilation was not improved by hE-Hb-B10 treatment, the peptide shifted vascular response in favor of NO-dependent vasodilation in SS mice. Taken together, these data demonstrate that hE-Hb-B10 decreases CF-Hb with a concomitant reduction in liver injury and changes in vascular response. Therefore, hE-Hb-B10 can be used to investigate the different roles of CF-Hb in hemolytic pathology and may have therapeutic benefit in the treatment of CF-Hb-mediated tissue damage. |
| Databáze: | OpenAIRE |
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