Hemopexin-dependent heme uptake via endocytosis regulates the Bach1 transcription repressor and heme oxygenase gene activation

Hada, Hiroshi; Shiraki, Takuma; Watanabe-Matsui, Miki; Igarashi, Kazuhiko

doi:10.1016/j.bbagen.2014.02.029

Cited by 16 publications

(9 citation statements)

References 58 publications

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“…Thus, Hx may be applied as a human blood-derived product, similar to other plasma proteins, such as albumin, α1-antitrypsin or immunoglobulins, which are well-established therapies. Alternatively, it is also feasible that Hx might become available as a recombinant protein (Satoh et al, 1994; Hada et al, 2014). Potential side effects of Hx treatment may be caused by its known protease activity, which has been associated with inhibition of leukocyte chemotaxis and increased mortality in a mouse model (Cheung et al, 1999; Bakker et al, 2005; Spiller et al, 2011).…”

Section: Protection Against Heme Toxicity Via Hemopexin and The Heme mentioning

confidence: 99%

Heme as a Target for Therapeutic Interventions

et al. 2017

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Heme is a complex of iron and the tetrapyrrole protoporphyrin IX with essential functions in aerobic organisms. Heme is the prosthetic group of hemoproteins such as hemoglobin and myoglobin, which are crucial for reversible oxygen binding and transport. By contrast, high levels of free heme, which may occur in various pathophysiological conditions, are toxic via pro-oxidant, pro-inflammatory and cytotoxic effects. The toxicity of heme plays a major role for the pathogenesis of prototypical hemolytic disorders including sickle cell disease and malaria. Moreover, there is increasing appreciation that detrimental effects of heme may also be critically involved in diseases, which usually are not associated with hemolysis such as severe sepsis and atherosclerosis. In mammalians homeostasis of heme and its potential toxicity are primarily controlled by two physiological systems. First, the scavenger protein hemopexin (Hx) non-covalently binds extracellular free heme with high affinity and attenuates toxicity of heme in plasma. Second, heme oxygenases (HOs), in particular the inducible HO isozyme, HO-1, can provide antioxidant cytoprotection via enzymatic degradation of intracellular heme. This review summarizes current knowledge on the pathophysiological role of heme for various diseases as demonstrated in experimental animal models and in humans. The functional significance of Hx and HOs for the regulation of heme homeostasis is highlighted. Finally, the therapeutic potential of pharmacological strategies that apply Hx and HO-1 in various clinical settings is discussed.

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Section: Protection Against Heme Toxicity Via Hemopexin and The Heme mentioning

confidence: 99%

Heme as a Target for Therapeutic Interventions

et al. 2017

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“…The heme that is transported from the blood stream to the liver and macrophages by Hx is catabolized by anti-inflammatory gene, heme oxygenase 1 (HO-1) (11, 12). Heme has been shown to induce the expression of HO-1 by inactivating the transcription repressor Bach1 through direct binding (13). However, the source of heme for the regulation of the Bach1-HO-1 axis had been unclear.…”

Section: Introductionmentioning

confidence: 99%

“…Since extracellular heme exists as a complex with Hx in serum under the physiological conditions, Hada et al . (13) examined the effects of (recombinant) rHx-bound heme on HO-1 expression and Bach1 in Hepa-1c1c7 liver cells as well as THP-1 macrophage cells. Hada et al demonstrated that rHx-bound heme was internalized into the cells via endocytosis, resulting in HO-1 expression and inactivation of Bach1, suggesting that i) induction of HO-1 expression is Hx-dependent and ii) Hx plays an antiatherogenic role.…”

Section: Introductionmentioning

confidence: 99%

Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases

Mehta

Reddy

2015

Current Opinion in Lipidology

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Purpose of the review Hemoglobin (Hb) and its scavenger proteins haptoglobin (Hp) and hemopexin (Hx) associate with HDL and influence the inflammatory properties of HDL. Moreover, HDL from Hx-null mice is proinflammatory. In addition, Hx deficiency is implicated in a number of other inflammatory diseases such as septic shock and experimental autoimmune encephalomyelitis. This review highlights studies that demonstrate novel insights into the physiological protective role of hemopexin in inflammatory diseases. Recent findings Recent studies demonstrate that Hx-dependent uptake of extracellular heme leads to the de-activation of Bach1 repression leading to the transcriptional activation of anti-oxidant HO-1 gene. Levels of circulating Hx have been implicated in the prognosis for patients with septic shock. In addition, Hx therapy has been shown to be beneficial in cardiovascular disease, cerebral ischemic injury and experimental autoimmune encephalomyelitis. Summary These studies suggest that heme scavenging is a major mechanism by which Hx defends against oxidative stress and related inflammatory disorders. Hx therapy may provide a novel protective role against heme and oxidative stress mediated inflammatory conditions including atherosclerosis.

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“…LRP1 is expressed in several cell types including hepatocytes, macrophages, neurons, and syncytiotrophoblasts. Hada et al [80] confirmed that hepatocytes and macrophages are able to take up the hemopexin-heme complex. Uptake of hemopexin-bound heme but not free heme was inhibited by treating the cells with the inhibitor of clathrin-mediated endocytosis, validating that the hemopexin-heme complex enters cells through endocytosis [80].…”

Section: Intercellular Heme Transportmentioning

confidence: 70%

Regulation of heme biosynthesis and transport in metazoa

Sun

Cheng

Chen

2015

Sci. China Life Sci.

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Heme is an iron-containing tetrapyrrole that plays a critical role in regulating a variety of biological processes including oxygen and electron transport, gas sensing, signal transduction, biological clock, and microRNA processing. Most metazoan cells synthesize heme via a conserved pathway comprised of eight enzyme-catalyzed reactions. Heme can also be acquired from food or extracellular environment. Cellular heme homeostasis is maintained through the coordinated regulation of synthesis, transport, and degradation. This review presents the current knowledge of the synthesis and transport of heme in metazoans and highlights recent advances in the regulation of these pathways. heme, iron, synthesis, transport, regulation Citation:Sun FX, Cheng YJ, Chen CY. Regulation of heme biosynthesis and transport in metazoa.

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Hemopexin-dependent heme uptake via endocytosis regulates the Bach1 transcription repressor and heme oxygenase gene activation

Cited by 16 publications

References 58 publications

Heme as a Target for Therapeutic Interventions

Heme as a Target for Therapeutic Interventions

Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases

Regulation of heme biosynthesis and transport in metazoa

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