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

Abstract

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.

Revisiting the interaction of heme with hemopexin: Recommendations for the responsible use of an emerging drug

“…In summary, we re-evaluate the heme-hemopexin interaction and propose a new K D value together with a heme-recruiting mechanism. These novel insights may contribute valuable information regarding hemopexin’s function and applicability that are currently under investigation in other laboratories, such as its antithrombotic and antiinflammatory effect 20,43,47 . While hemopexin is currently being considered for the treatment of intracerebral hemorrhage (ICH) 48 , it might also be administered for the therapy of heme overload conditions, such as in sickle cell disease or β-thalassemia 47,49,50 .…”

“…Hemopexin plays a major role in humans by detoxifying heme and preventing organismal damage under hemolytic conditions 5 . Several reports show its applicability as therapeutic agent 5,19,20,42,43 . This advancement in the medical application of hemopexin stands in strong contrast to the knowledge available regarding the exact nature of the heme-hemopexin interaction.…”

“…Consequently, researchers sought to apply hemopexin as therapeutic agent when the bodies’ heme-scavenging capacity is exhausted. There are abundant model systems of human diseases, in which hemopexin administration improved clinical parameters, which have been reviewed elsewhere 20 . These promising results currently fuel commercial interest in plasma-derived hemopexin as potential treatment for e.g., sickle cell disease.…”

Effects of Different Dietary Vegetable Lipid Sources on Health Status in Nile Tilapia (Oreochromis niloticus): Haematological Indices, Immune Response Parameters and Plasma Proteome

“…Hemopexin (HPX) is a glycoprotein in plasma which binds to free heme and; therefore, plays an important role in detoxifying heme and lipid oxidation [ 44 ]. Plasma HPX level is; therefore, an important biomarker for inflammatory and oxidative stress [ 45 , 46 ]. Our results showed that dietary PO increased plasma HPX levels.…”

Iron as Therapeutic Target in Human Diseases

“…While this review summarized the data on Tfr2 extrahepatic role, including the importance of the two main isoforms, Tfr2α and Tfr2β, the use of Tfr2 as therapeutic target for hepcidin control is also discussed. Finally, the systemic iron regulation, achieved by controlling heme metabolism, was described by Montecinos et al [25], who reviewed the present knowledge on the heme-binding protein hemopexin (HPX) and provided information on its biochemistry. HPX prevents the toxicity induced by hemoglobin (Hb)-derived heme, which occurs in hemolytic conditions and can be triggered by the activation of the immune system.…”