The increase in pulmonary arterial pressure caused by hypoxia depends on iron status

Abstract

Hypoxia is a major cause of pulmonary hypertension. Gene expression activated by the transcription factor hypoxia-inducible factor (HIF) is central to this process. The oxygen-sensing iron-dependent dioxygenase enzymes that regulate HIF are highly sensitive to varying iron availability. It is unknown whether iron similarly influences the pulmonary vasculature. This human physiology study aimed to determine whether varying iron availability affects pulmonary arterial pressure and the pulmonary vascular response to hypoxia, as predicted biochemically by the role of HIF. In a controlled crossover study, 16 healthy iron-replete volunteers undertook two separate protocols. The 'Iron Protocol' studied the effects of an intravenous infusion of iron on the pulmonary vascular response to 8 h of sustained hypoxia. The 'Desferrioxamine Protocol' examined the effects of an 8 h intravenous infusion of the iron chelator desferrioxamine on the pulmonary circulation. Primary outcome measures were pulmonary artery systolic pressure (PASP) and the PASP response to acute hypoxia (DeltaPASP), assessed by Doppler echocardiography. In the Iron Protocol, infusion of iron abolished or greatly reduced both the elevation in baseline PASP (P < 0.001) and the enhanced sensitivity of the pulmonary vasculature to acute hypoxia (P = 0.002) that are induced by exposure to sustained hypoxia. In the Desferrioxamine Protocol, desferrioxamine significantly elevated both PASP (P < 0.001) and DeltaPASP (P = 0.01). We conclude that iron availability modifies pulmonary arterial pressure and pulmonary vascular responses to hypoxia. Further research should investigate the potential for therapeutic manipulation of iron status in the management of hypoxic pulmonary hypertensive disease.

Figures

Figure 1. Schematic representation of experimental protocols

Each protocol was conducted over two separate days. For the Iron Protocol, a control infusion of normal saline was administered on the first experimental day and an infusion of iron sucrose was given on the second experimental day. For the DFO Protocol, a control infusion of normal saline was administered on one experimental day and an infusion of desferrioxamine (DFO) was given on the other experimental day. Pulmonary artery pressure was assessed echocardiographically during the acute hypoxic challenges. denotes end-tidal partial pressure of oxygen.

Figure 2. Effects of 8 h of sustained hypoxia on pulmonary artery systolic pressure with and without prior infusion of iron

Upper panels show end-tidal partial pressures of oxygen () and carbon dioxide () during acute hypoxic challenges. Lower panels show corresponding measurements of pulmonary artery systolic pressure (PASP). Values are means and error bars indicate s.e.m. The control measurements demonstrate the normal pulmonary vascular response to sustained hypoxia, consisting of an increase in PASP and a sensitized PASP response to subsequent acute hypoxia (ΔPASP). Intravenous infusion of iron prior to the 8 h hypoxic exposure prevented the increase in baseline PASP (P < 0.001) and markedly attenuated the degree to which ΔPASP was sensitized (P = 0.002).

Figure 3. Effects of an 8 h infusion of desferrioxamine on pulmonary artery systolic pressure

Upper panels show end-tidal partial pressures of oxygen () and carbon dioxide () during acute hypoxic challenges. Lower panels show corresponding measurements of pulmonary artery systolic pressure (PASP). DFO denotes desferrioxamine. Values are means and error bars indicate s.e.m. Infusion of DFO increased PASP (P < 0.001) and sensitized the pulmonary vascular response to acute hypoxia (P = 0.01).