Pulmonary Arterial Hypertension: Iron Matters

Abstract

The interplay between iron and oxygen is longstanding and central to all aerobic life. Tight regulation of these interactions including homeostatic regulation of iron utilization ensures safe usage of this limited resource. However, when control is lost adverse events can ensue, which are known to contribute to an array of disease processes. Recently, associations between disrupted iron homeostasis and pulmonary artery hypertension (PAH) have been described with the suggestion that there is a contributory link with disease. This review provides a background for iron regulation in humans, describes PAH classifications, and discusses emerging literature, which suggests a role for disrupted iron homeostatic control in various sub-types of PAH, including a role for decompartmentalization of hemoglobin. Finally, the potential for therapeutic options to restore iron homeostatic balance in PAH are discussed.

Keywords: hepcidin and ferroportin 1 (Fpn1); iron; pulmonary arterial hypertension; pulmonary arterial remodeling; pulmonary hypertension.

FIGURE 1

Effects of hepcidin on iron homeostasis. Schematic representation of the effects of hepcidin on dietary absorption of iron (left) and intracellular iron stores (right). Fpn, ferroportin; Tf, transferrin; Fe, iron; Hb, hemoglobin; NTBI, non-transferrin-bound iron.

FIGURE 2

Control of hepcidin expression. Schematic representation of the factors controlling hepcidin transcription. IL-6, interleukin 6; JAK/STAT3, Janus kinase/signal transducers and activator of transcription 3; Fe, iron; TfR, transferrin receptor; HIF, hypoxia-inducible factor; GDF-15, growth/differentiation factor 15; BMPR, bone morphogenetic protein receptor; Fpn, ferroportin.

FIGURE 3

Remodeled pulmonary arteriole from a patient with idiopathic pulmonary arterial hypertension taken after transplant. Remodeling in this case is characterized by an increase in the number of smooth muscle cells in the media. The endothelium is stained with an anti-vWF antibody (brown stain). vWF, von Willibrand Factor. Figure courtesy of Dr. Allan Lawrie and Dr. Roger Thompson, University of Sheffield, United Kingdom.