Heme as a Target for Therapeutic Interventions.

Stephan Immenschuh,Vijith Vijayan,Faikah Gueler,Sabina Janciauskiene

doi:10.3389/fphar.2017.00146

Abstract

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.

Highlights

Heme is a ubiquitous molecular complex of iron and the tetrapyrrole protoporphyrin IX
Heme in plasma from patients with atypical hemolytic uremic syndrome activated the alternative pathway of the complement cascade, which in turn caused endothelial cell activation (Frimat et al, 2013). These findings suggest that heme may have similar effects in the pathophysiology of other vascular inflammatory diseases
2009 Belcher et al, 2006 in vitro and in vivo studies have revealed that specific upregulation of heme oxygenases (HOs)-1 via heme or low doses of Hb provide beneficial effects in various preclinical models of experimental pathological conditions such as endotoxin-mediated lung injury in rats (Otterbein et al, 1995), human immunodeficiency syndrome (Levere et al, 1991; Devadas and Dhawan, 2006) or diabetes (Ndisang et al, 2009)

Summary

Introduction

Heme is a ubiquitous molecular complex of iron and the tetrapyrrole protoporphyrin IX. In mouse models of experimental malaria release of extracellular Hb and heme from damaged RBCs had major pro-oxidant and pro-inflammatory effects.

Results

Conclusion