학술논문
Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension
Document Type
article
Author
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; R. Scott Pearsall; Patrick Andre; Paul B. Yu; Ravindra Kumar; Gang Li
Source
Scientific Reports, Vol 12, Iss 1, Pp 1-18 (2022)
Subject
Language
English
ISSN
2045-2322
Abstract
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 structure and function in Bmpr2 haploinsufficient mice subjected to hypoxia, a model of heritable PAH. Three high-affinity ligands of ActRIIA-Fc each induced macrophage activation in vitro, and their combined immunoneutralization in PAH rats produced cardiopulmonary benefits comparable to those elicited by ActRIIA-Fc. Our results in complementary experimental and genetic models of PAH reveal therapeutic anti-inflammatory activities of ActRIIA-Fc that, together with its known anti-proliferative effects on vascular cell types, could underlie clinical activity of sotatercept as either monotherapy or add-on to current PAH therapies.