Iron Homeostasis and Pulmonary Hypertension: Iron Deficiency Leads to Pulmonary Vascular Remodeling in the Rat
Rationale: Iron deficiency without anaemia is prevalent in patients with idiopathic pulmonary arterial hypertension and associated with reduced exercise capacity and survival.
Objective: We hypothesised that iron deficiency is involved in the pathogenesis of pulmonary hypertension and iron replacement is a possible therapeutic strategy.
Methods and Results: Rats were fed an iron-deficient diet (IDD, 7mg/kg) and investigated over 4 weeks. Iron deficiency was evident from depleted iron stores (decreased liver, serum iron and ferritin), reduced erythropoiesis and significantly decreased transferrin saturation and lung iron stores after 2 weeks IDD. IDD rats exhibited profound pulmonary vascular remodelling with prominent muscularization, medial hypertrophy and perivascular inflammatory cell infiltration, associated with raised pulmonary artery pressure and right ventricular hypertrophy. IDD rat lungs demonstrated increased expression of HIF1α and HIF2α, NFAT and survivin, and STAT3 activation, which promote vascular cell proliferation and resistance to apoptosis. Biochemical examination showed reduced mitochondrial complex I activity and mitochondrial membrane hyperpolarisation in mitochondria from IDD rat pulmonary arteries. Along with upregulation of the glucose transporter, GLUT1, and glycolytic genes, hk1 and pdk1, lung 18FDG uptake was significantly increased in IDD rats. The hemodynamic and pulmonary vascular remodelling were reversed by iron replacement (ferric carboxymaltose, 75mg/Kg) and attenuated in the presence of iron deficiency by dichloroacetate and imatinib, two putative treatments explored for PAH that target aerobic glycolysis and proliferation, respectively.
Conclusions: These data suggest a major role for iron in pulmonary vascular homeostasis and support the clinical evaluation of iron replacement in patients with pulmonary hypertension.
- Received September 13, 2014.
- Revision received February 19, 2015.
- Accepted March 12, 2015.