Heme as a Target for Therapeutic Interventions

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.

Keywords: heme; heme oxygenases; heme toxicity; hemolysis; hemopexin; inflammation; inflammatory diseases.

Figure 1

Schematic on cell-type specific effects of heme toxicity and its role in the pathogenesis of diseases. Free heme can arise in hemolysis from cell-free hemoglobin (Hb) oxidized to Met-Hb and in tissue damage and injury from intracellular hemoproteins that are released from cells such as myoglobin. Heme has pro-oxidant, pro-inflammatory and cytotoxic effects and can cause cell type-specific effects in endothelial cells and monocytes/macrophages. Heme is involved in the pathogenesis of various hemolytic diseases including sickle cell disease (SCD) and malaria, but also in disorders that are not typically associated with hemolysis. CNS, central nervous system; NLRP3, nucleotide-binding domain and leucine-rich repeat pyrin 3 containing; TLR, toll-like receptor.

Figure 2

Therapeutic interventions for the neutralization of heme. The antioxidant scavenger proteins haptoglobin (Hp) and hemopexin (Hx) bind and neutralize extracellular Hb and free heme in plasma, respectively. HO-1 is the inducible isoform of HOs, which enzymatically degrade intracellular heme to produce iron, carbon monoxide and biliverdin, which is converted into bilirubin by biliverdin reductase. Hx and Hp may be applied as a potential heme-neutralizing therapy via systemic intravenous administration. Potential therapies of HO-1 may be performed via targeted pharmacological induction. LRP1, low density lipoprotein receptor-related protein 1.