Hemopexin · Lablypedia

Hemoglobin itself circulating alone in the blood plasma (called free hemoglobin, as opposed to the hemoglobin situated in and circulating with the red blood cell.) will soon be oxidized into met-hemoglobin which then further disassociates into free heme along with globin chain. The free heme will then be oxidized into free met-heme and sooner or later the hemopexin will come to bind free met-heme together, forming a complex of met-heme and hemopexin, continuing their journey in the circulation until reaching a receptor, such as LRP1, on hepatocytes or macrophages within the spleen, liver and bone marrow.

Hemopexin's arrival and subsequent binding to the free heme not only prevent heme's pro-oxidant and pro-inflammatory effects but also promotes free heme's detoxification.

Hemopexin is different from haptoglobin, the latter always binds to free hemoglobin. (See Haptoglobin § Differentiation with hemopexin)

Cloning, expression, and discovery

Takahashi et al. (1985) determined that human plasma hemopexin consists of a single polypeptide chain of 439 amino acids residues with six intrachain disulfide bridges and has a molecular mass of approximately 63 kD. The amino-terminal threonine residue is modified by a mucin-type O-linked galactosamine oligosaccharide, and the protein has five N-linked glycan modifications. The 18 tryptophan residues are arranged in four clusters, and 12 of the tryptophans are conserved in homologous positions. Computer-assisted analysis of the internal homology in amino acid sequence suggested duplication of an ancestral gene thus indicating that hemopexin consists of two similar halves.

Altruda et al. (1988) demonstrated that the HPX gene spans approximately 12 kb and is interrupted by 9 exons. The demonstration shows direct correspondence between exons and the 10 repeating units in the protein. The introns were not placed randomly; they fell in the center of the region of amino acid sequence homology in strikingly similar locations in 6 of the 10 units and in a symmetric position in each half of the coding sequence. From these observations, Altruda et al. (1988) concluded that the gene evolved through intron-mediated duplications of a primordial sequence to a 5-exon cluster.

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Mapping of hemopexin gene

Cai and Law (1986) prepared a cDNA clone for hemopexin, by Southern blot analysis of human/hamster hybrids containing different combinations of human chromosomes, assigned the HPX gene to human chromosome 11. Law et al. (1988) assigned the HPX gene to 11p15.5-p15.4, the same location as that of the beta-globin gene complex by in situ hybridization.

Differential transcriptional pattern of hemopexin gene

In 1986, the expression of the human HPX gene in different human tissues and cell lines was carried out by using a specific cDNA probe. From the results obtained it was concluded that this gene was expressed in the liver and it was below the level of detection in other tissues or cell lines examined. By S1 mapping, the transcription initiation site in hepatic cells was located 28 base pairs upstream from the AUG initiation codon of the hemopexin gene.

Function

Hemopexin binds heme with the highest affinity of any known protein. Its main function is scavenging the heme released or lost by the turnover of heme proteins such as hemoglobin and thus protects the body from the oxidative damage that free heme can cause. In addition, hemopexin releases its bound ligand for internalisation upon interacting with CD91. Hemopexin preserves the body's iron. Hemopexin -dependent uptake of extracellular heme can lead to the deactivation of Bach1 repression which leads to the transcriptional activation of antioxidant heme oxygenase-1 gene. Hemoglobin, haptoglobin (Hp) and Hx associate with high density lipoprotein (HDL) and influence the inflammatory properties of HDL. Hemopexin can downregulate the angiotensin II Type 1 receptor (AT1-R) in vitro.

Clinical significance

The predominant source of circulating hemopexin is the liver with a plasma concentration of 1–2 mg/ml. Serum hemopexin level reflects how much heme is present in the blood. Therefore, a low hemopexin level indicates that there has been significant degradation of heme containing compounds. A low hemopexin level is one of the diagnostic features of an intravascular hemolytic anemia. Hemopexin has been implicated in cardiovascular disease, septic shock, cerebral ischemic injury, and experimental autoimmune encephalomyelitis. The circulating level of hemopexin is associated with prognosis in patients with septic shock.

HPX is also produced in the brain. Deletion of the HPX gene can aggravate brain injury followed by stroma-free hemoglobin-induced intracerebral haemorrhage. High hemopexin level in the cerebrospinal fluid is associated with poor outcome after subarachnoid hemorrhage.

Circulating hemopexin can modulate anthracycline-induced cardiotoxicity (e.g. heart failure) in both humans and mice.

Relation to haptoglobin

In past there have been reports showing that in patients with sickle cell disease, spherocytosis, autoimmune hemolytic anemia, erythropoietic protoporphyria and pyruvate kinase deficiency, a decline in hemopexin concentration occurs in situations when haptoglobin (Hp) concentrations are low or depleted as a result of severe or prolonged hemolysis. Both haptoglobin and hemopexin are acute-phase proteins, the synthesis of which are induced during infection and after inflammatory states to minimize tissue injury and facilitate tissue repair. Hp and hemopexin prevent heme toxicity by binding themselves to heme prior to monocyte or macrophage's arrivals and ensuing clearances, which may explain their effects on outcome in several diseases, and underlies the rationale for exogenous haptoglobin and hemopexin as therapeutic proteins in hemolytic or hemorrhagic conditions. Hemopexin is the major vehicle for the transportation of heme in the plasma.