RT Journal Article SR Electronic T1 Intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice JF Proceedings of the National Academy of Sciences JO Proc Natl Acad Sci USA FD National Academy of Sciences SP 13122 OP 13130 DO 10.1073/pnas.1822010116 VO 116 IS 26 A1 Lakhal-Littleton, Samira A1 Crosby, Alexi A1 Frise, Matthew C. A1 Mohammad, Goran A1 Carr, Carolyn A. A1 Loick, Paul A. M. A1 Robbins, Peter A. YR 2019 UL http://www.pnas.org/content/116/26/13122.abstract AB Pulmonary arterial hypertension (PAH) is a disease in which lung blood pressure is raised chronically, causing right heart failure. It has been shown that iron deficiency also raises lung blood pressure. However, we don’t know the mechanisms because we don’t understand precisely how cells of the lung blood vessels are affected by iron levels. The smooth muscle cells of the lung blood vessels are important for controlling lung blood pressure. Our study shows that iron deficiency specifically within these cells is sufficient to cause PAH, even against a background of normal iron levels in other tissues.Iron deficiency augments hypoxic pulmonary arterial pressure in healthy individuals and exacerbates pulmonary arterial hypertension (PAH) in patients, even without anemia. Conversely, iron supplementation has been shown to be beneficial in both settings. The mechanisms underlying the effects of iron availability are not known, due to lack of understanding of how cells of the pulmonary vasculature respond to changes in iron levels. The iron export protein ferroportin (FPN) and its antagonist peptide hepcidin control systemic iron levels by regulating release from the gut and spleen, the sites of absorption and recycling, respectively. We found FPN to be present in pulmonary arterial smooth muscle cells (PASMCs) and regulated by hepcidin cell autonomously. To interrogate the importance of this regulation, we generated mice with smooth muscle-specific knock in of the hepcidin-resistant isoform fpn C326Y. While retaining normal systemic iron levels, this model developed PAH and right heart failure as a consequence of intracellular iron deficiency and increased expression of the vasoconstrictor endothelin-1 (ET-1) within PASMCs. PAH was prevented and reversed by i.v. iron and by the ET receptor antagonist BQ-123. The regulation of ET-1 by iron was also demonstrated in healthy humans exposed to hypoxia and in PASMCs from PAH patients with mutations in bone morphogenetic protein receptor type II. Such mutations were further associated with dysregulation of the HAMP/FPN axis in PASMCs. This study presents evidence that intracellular iron deficiency specifically within PASMCs alters pulmonary vascular function. It offers a mechanistic underpinning for the known effects of iron availability in humans.