Mouse Study Finds Causal Link Between Iron Levels and Pulmonary Hypertension
A new study in mice demonstrated that a lack of iron in muscle cells lining the circulatory system in the lungs — termed pulmonary arterial smooth muscle cells (PASMCs) — sets off a chain of events that result in pulmonary hypertension (PH).
These results suggest a cause-and-effect link between iron deficiency and PH.
The study, titled “Intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice,” was published in the journal Proceedings of the National Academy of Sciences.
Iron deficiency has a well-established link to PH, and iron supplementation has proven to be beneficial for some patients with the disease. Yet, the reasons for this connection have remained elusive.
Regulation of iron in the body is governed in large part by two proteins: ferroportin and hepcidin.
Ferroportin is a transport protein that can move iron from within a cell to the outside of a cell (i.e., into the bloodstream), allowing iron to be moved from organs like the gut and liver, where it is absorbed and stored, respectively, into the blood.
Hepcidin regulates this process by essentially turning ferroportin “off,” causing iron to remain within cells. Controlling the levels of this protein allows for the indirect control of iron released from cells.
PASMCs express both of these proteins, prompting the researchers to wonder if this might be the link between PH and iron regulation.
To find out, researchers developed mice that expressed a mutant version of ferroportin in their PASMCs (and only their PASMCs, so as to avoid off-target effects from systemic iron dysregulation). This mutant version is unresponsive to hepcidin; essentially, it is stuck in a perpetual “on” state of moving iron out of the cells. Indeed, researchers confirmed that PASMCs in these mice had lower levels of iron within the cell than did normal mice.
Importantly, these mice developed PH and right-sided heart failure, suggesting that decreasing the amount of iron in these cells contributes to PH development.
Further supporting this association, mice with the mutation that were given injections of iron — which was able to restore iron in PASMCs to near-normal levels — had fewer signs of PH and heart failure. This “rescue effect” was more pronounced when iron was given earlier, suggesting that, while iron supplementation can help prevent the development of PH in these mice, it cannot reverse the damage already done.
Having identified this relationship, the researchers next wondered how iron levels in PASMCs might actually cause PH. They found that another protein, ET-1, was present at higher levels in iron-deficient PASMCs, leading them to hypothesize that this protein might be the culprit.
To test this, the team treated the aforementioned mice with mutant ferroportin with an inhibitor of ET-1. This produced a similar prevention-but-not-reversal result, as with iron injections, supporting ET-1 as a mechanism by which iron deficiency can cause PH.
Finally, the researchers asked whether this dysregulation in iron levels also could cause some familial cases of PH. Specifically, they were interested in BMPR2, a protein that is involved in regulating the production of hepcidin levels. Some mutations in the BMPR2 gene are known to be associated with familial PH.
Testing one such mutation (R899X) in mouse and human cells, researchers found that cells with this mutation made less hepcidin and, consequently, produced more ferroportin and ET-1. This supports a link between mutations in BMPR2 and the development of PH via iron-based pathways.
Overall, “this study presents evidence that intracellular iron deficiency specifically within PASMCs alters pulmonary vascular function,” the researchers wrote.
“We also provide evidence that BMPR2 mutations are associated with reduced hepcidin expression in PASMCs, and consequently increased FPN [ferroportin] and ET-1 levels. These effects could constitute an additional mechanistic link between BMPR2 mutations” and familial PH, the team added.