01 March 2017 by Jeffrey Robinson

Iron deficiency in hypoxic pulmonary hypertension results in increased circulating erythropoietin which is associated with attenuated pulmonary hypertension

Rationale

Iron deficiency in pulmonary arterial hypertension (PAH) is prevalent and associated with worsened morbidity
and mortality. However, in models of pulmonary hypertension (PH), there is conflicting data regarding whether
iron deficiency is protective or pathogenic in PH. We have demonstrated a protective effect of iron deficiency in
a murine model of PH, and hypothesize that the protective effect is driven by increased renal expression of
erythropoietin (EPO), which acts in a paracrine manner to attenuate PH.

Methods

C57BL6 mice were exposed to 3 weeks of normoxia (Nx) or hypoxia (Hx) (10% FiO2, at Denver barometric
pressure), in addition to either normal diet (ND) or iron deficient diet/environment (FeD). The animals then
underwent terminal right ventricular catheterization. Whole lung and renal tissue, as well as serum was utilized
for analysis of hypoxia inducible factor (HIF) transcripts/protein. Finally, intraperitoneally-dosed soluble EPOreceptor
(sEPO-R) and vehicle was given to animals exposed to hypoxia and iron deficient conditions.

Results

Under hypoxic conditions, iron deficiency led to significant attenuation of RVSP (NxND=19.11 mmHg,
HxND=32.6 mmHg, HxFeD=25.82 mmHg, p < 0.05). In lung tissue we saw the expected rise in HIF target
gene transcript levels in hypoxia, but this was not altered by iron deficiency. However, we saw a significant rise
in circulating EPO in HxFeD (serum, Nx=211.3 ng, Hx=536.0 ng, Hx+FeD=2340 ng). With blockade of
circulating erythropoietin utilizing sEPO-R, we saw restoration of the PH phenotype in HxFeD
(HxFeD+vehicle=27.03 mmHg, HxFeD+sEPO-R=37.84 mmHg).

Conclusions

We have demonstrated that iron deficiency exerts a protective effect in experimental PH. Iron deficiency with
hypoxia increases renal HIF activity resulting in significant increases in EPO expression, which may exert
protective pleiotropic effects on the pulmonary vasculature, resulting in attenuation of hypoxic rise in RVSP.
Future work will delineate the mechanisms by which EPO-signaling modulates the pulmonary vasculature.

About the author


profile picture of Jeffrey Robinson

Jeffrey Robinson

Assistant Professor

University of Colorado

United States

Key Contributors

Robinson JC, Dailey K, Kumar R, Graham BB, Tuder RM. Program in Translational Lung Research, University of Colorado Denver


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