Researchers showed that sotatercept, an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein used in patients with pulmonary arterial hypertension (PAH), normalizes macrophage infiltration and reverses inflammation and proliferative gene expression in PAH rats.

They noted that vasodilators such as the phosphodiesterase type 5 inhibitor sildenafil did not have the same beneficial effects on diseased rat lungs, as published in Scientific Reports.

“There is a growing consensus that early and persistent inflammation and altered immune responses underlie PAH pathophysiology,” the authors wrote.


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“Our results demonstrate that inflammatory gene signatures and macrophage perivascular infiltrates in severe experimental PAH were normalized by therapeutic treatment with ActRIIA-Fc, and the concordance we observed between aberrant gene profiles in this rodent model and in PAH patients strongly supports the translatability of these findings to human PAH.”

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Given that there are occasional cases of a complete reversal in PAH, there is hope that a therapeutic approach can be developed to reverse cardiopulmonary remodeling in these patients. The research team compared the effects of ActRIIA-Fc with the vasodilator sildenafil and observed significantly greater anti-inflammatory action by ActRIIA-Fc.

However, the authors caution that further studies will be required to compare ActRIIA-Fc with other classes of vasodilators and also to assess the effect of combined treatment in patients with PAH.

The study results showed that there was concordance between aberrant gene profiles in the rat model and in patients with PAH, suggesting a strong likelihood that the findings will be translatable to human PAH. Furthermore, the beneficial effects lasted for at least 1 month after cessation of treatment, which suggests that ActRIIA-Fc might be disease-modifying.

Reference

Joshi SR, Liu J, Bloom T, et al. Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension. Sci Rep. Published online May 12, 2022. doi:10.1038/s41598-022-11435-x