Protection against Heme Toxicity: Hemopexin Rules, OK?

Smith, Ann

doi:10.1142/9789814407755_0045

Cited by 6 publications

(26 citation statements)

References 159 publications

(322 reference statements)

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“…In humans, a relationship between HO1 activity and HPX metabolism was first apparent in HO1-deficiency with undetectable HPX levels in a child that succumbed by 6 years (Yachie et al, 1999 ), as previously reviewed (Smith, 2011b , 2013 ); and which is recapitulated in part, in HO1 −/− mice that also have low HPX (Kovtunovych et al, 2010 ). In both situations, the key role for macrophage HO1 activity for heme catabolism and subsequent safe iron distribution in the body with minimal inflammation is apparent.…”

Section: The Clearance Of Hemoglobin By Hemopexin and Haptoglobin Durmentioning

confidence: 90%

“…HPX protects human endothelial (Balla et al, 1993 ) and hepatic parenchymal (Larsen et al, 2010 ) cells from direct heme toxicity and heme-sensitization (Balla et al, 1991b ). HPX protects human macrophages by limiting the heme-mediated oxidation of lipoproteins (Camejo et al, 1998 ; Smith, 2013 ) generating lipid peroxide- and iron loaded-LDL (Balla et al, 1991a ). Heme-mediated LDL oxidation contributes to the pathogenesis of atherosclerosis (Camejo et al, 1998 ; Jeney et al, 2002 ), heme being derived from ruptured plaques (Nagy et al, 2010 ) and LDL from the extracellular intima.…”

Section: Introductionmentioning

confidence: 99%

“…Interest in the protective role of HPX has rapidly increased during the past 5 years because the causative role of heme in the pathophysiology of sepsis, sickle cell disease (SCD), other hemolytic conditions and also in atherosclerosis (Balla et al, 1991a ; Nagy et al, 2010 ) has become accepted (Larsen et al, 2010 ; Smith, 2011a , b ; Ghosh et al, 2013 ; Schaer et al, 2013 ; Smith, 2013 ; Belcher et al, 2014 ; Schaer et al, 2014 ; Jung et al, 2015 ). Insights into how HPX acts in clinical IVH and EVH have been obtained primarily through primate-, rat-, mouse-, and human-based studies.…”

Section: Introductionmentioning

confidence: 99%

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Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders

2015

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The goal here is to describe our current understanding of heme metabolism and the deleterious effects of “free” heme on immunological processes, endothelial function, systemic inflammation, and various end-organ tissues (e.g., kidney, lung, liver, etc.), with particular attention paid to the role of hemopexin (HPX). Because heme toxicity is the impetus for much of the pathology in sepsis, sickle cell disease (SCD), and other hemolytic conditions, the biological importance and clinical relevance of HPX, the predominant heme binding protein, is reinforced. A perspective on the function of HPX and haptoglobin (Hp) is presented, updating how these two proteins and their respective receptors act simultaneously to protect the body in clinical conditions that entail hemolysis and/or systemic intravascular (IVH) inflammation. Evidence from longitudinal studies in patients supports that HPX plays a Hp-independent role in genetic and non-genetic hemolytic diseases without the need for global Hp depletion. Evidence also supports that HPX has an important role in the prognosis of complex illnesses characterized predominantly by the presence of hemolysis, such as SCD, sepsis, hemolytic-uremic syndrome, and conditions involving IVH and extravascular hemolysis (EVH), such as that generated by extracorporeal circulation during cardiopulmonary bypass (CPB) and from blood transfusions. We propose that quantitating the amounts of plasma heme, HPX, Hb-Hp, heme-HPX, and heme-albumin levels in various disease states may aid in the diagnosis and treatment of the above-mentioned conditions, which is crucial to developing targeted plasma protein supplementation (i.e., “replenishment”) therapies for patients with heme toxicity due to HPX depletion.

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Section: The Clearance Of Hemoglobin By Hemopexin and Haptoglobin Durmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders

2015

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“…The responses involve complex biochemical systems with multi-factorial processes that may even drive pathology in cancer. Hemopexin has been linked to various cancers (reviewed in Reference [74]) and approximately half of deaths of cancer patients with malignant tumors are associated with thrombotic events. Vascular occlusive diseases include atherosclerosis and lead to carotid artery disease and heart attacks, which is a leading cause of death in developed countries.…”

Section: Hpx Status In Platelets In Hemostasis and Thrombosismentioning

confidence: 99%

“…Several changes in carbohydrate structure of glycoproteins have been linked to liver disease [74] and another means to monitor liver disease utilizes identification of aberrant core fucosylation of plasma glycoproteins as biomarkers. Such alterations are readily assessed from patient serum samples.…”

Section: Liver Disease/injurymentioning

confidence: 99%

What Is Next in This “Age” of Heme-Driven Pathology and Protection by Hemopexin? An Update and Links with Iron

2019

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This review provides a synopsis of the published literature over the past two years on the heme-binding protein hemopexin (HPX), with some background information on the biochemistry of the HPX system. One focus is on the mechanisms of heme-driven pathology in the context of heme and iron homeostasis in human health and disease. The heme-binding protein hemopexin is a multi-functional protectant against hemoglobin (Hb)-derived heme toxicity as well as mitigating heme-mediated effects on immune cells, endothelial cells, and stem cells that collectively contribute to driving inflammation, perturbing vascular hemostasis and blood–brain barrier function. Heme toxicity, which may lead to iron toxicity, is recognized increasingly in a wide range of conditions involving hemolysis and immune system activation and, in this review, we highlight some newly identified actions of heme and hemopexin especially in situations where normal processes fail to maintain heme and iron homeostasis. Finally, we present preliminary data showing that the cytokine IL-6 cross talks with activation of the c-Jun N-terminal kinase pathway in response to heme-hemopexin in models of hepatocytes. This indicates another level of complexity in the cell responses to elevated heme via the HPX system when the immune system is activated and/or in the presence of inflammation.

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Poly(ethylene glycol) Surface-Conjugated Apohemoglobin as a Synthetic Heme Scavenger

2020

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Apohemoglobin (apoHb) contains vacant hydrophobic heme-binding pockets that can bind to a variety of hydrophobic molecules. Thus, apoHb is a promising protein for drug delivery, bioimaging, and heme scavenging. Unfortunately, apoHb has a short half-life and precipitates at physiological temperature. In this study, apoHb was surface-conjugated with poly(ethylene glycol) (PEG) to improve the therapeutic potential of apoHb. The scalable PEGylation process had >95% protein yield with ∼10 to 12 PEGs attached to each apoHb αβ dimer. The resulting PEG-apoHb had an average molecular weight of ∼80 to 90 kDa and a hydrodynamic diameter of 11 nm. PEG-apoHb maintained high heme-binding affinity and 30−40% of the hemebinding activity. Moreover, heme-bound and heme-free PEG-apoHb bound to haptoglobin, enabling PEG-apoHb to potentially target CD163+ macrophages and monocytes. Finally, PEG-apoHb was stable at physiological temperature with minimal precipitation. In summary, the in vitro results shown demonstrate that PEG-apoHb could be an effective in vivo heme scavenger during states of hemolysis.

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Protection against Heme Toxicity: Hemopexin Rules, OK?

Cited by 6 publications

References 159 publications

Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders

Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders

What Is Next in This “Age” of Heme-Driven Pathology and Protection by Hemopexin? An Update and Links with Iron

Poly(ethylene glycol) Surface-Conjugated Apohemoglobin as a Synthetic Heme Scavenger

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