Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension
Sachindra R. Joshi, Jun Liu, Troy Bloom, Elif Karaca Atabay, Tzu-Hsing Kuo, Michael Lee, Elitza Belcheva, Matthew Spaits, Rosa Grenha, Michelle C. Maguire, Jeffrey L. Frost, Kathryn Wang, Steven D. Briscoe, Mark J. Alexander, Brantley R. Herrin, Roselyne Castonguay
TL;DR
A drug called sotatercept reduces inflammation and improves lung and heart function in a rat model of pulmonary arterial hypertension.
Contribution
The study reveals that sotatercept's anti-inflammatory effects, in addition to its known anti-proliferative actions, contribute to its therapeutic benefits in PAH.
Findings
ActRIIA-Fc reversed proinflammatory gene expression and macrophage infiltration in PAH rat lungs.
ActRIIA-Fc corrected cardiopulmonary structure and function in a genetic model of heritable PAH.
Neutralizing ActRIIA-Fc ligands produced similar benefits to ActRIIA-Fc treatment in PAH rats.
Abstract
Sotatercept is an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that improves cardiopulmonary function in patients with pulmonary arterial hypertension (PAH) by selectively trapping activins and growth differentiation factors. However, the cellular and molecular mechanisms of ActRIIA-Fc action are incompletely understood. Here, we determined through genome-wide expression profiling that inflammatory and immune responses are prominently upregulated in the lungs of a Sugen-hypoxia rat model of severe angio-obliterative PAH, concordant with profiles observed in PAH patients. Therapeutic treatment with ActRIIA-Fc—but not with a vasodilator—strikingly reversed proinflammatory and proliferative gene expression profiles and normalized macrophage infiltration in diseased rodent lungs. Furthermore, ActRIIA-Fc normalized pulmonary macrophage infiltration and corrected cardiopulmonary…
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Taxonomy
TopicsPulmonary Hypertension Research and Treatments · RNA modifications and cancer · Cardiac Fibrosis and Remodeling