Open AccessACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension
Author(s) -
Lai Ming Yung,
Peiran Yang,
Sachindra Raj Joshi,
Zachary M. Augur,
Stephanie S.J. Kim,
Geoffrey A. Bocobo,
Teresa Dinter,
Luca Troncone,
Po Sheng Chen,
Megan McNeil,
Mark Southwood,
S. Poli De Frias,
John L. Knopf,
Iván O. Rosas,
Dianne Sako,
R. Scott Pearsall,
John D. Quisel,
Gang Li,
Ravindra Kumar,
Paul B. Yu
Publication year - 2020
Publication title -
science translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.819
H-Index - 216
eISSN - 1946-6242
pISSN - 1946-6234
DOI - 10.1126/scitranslmed.aaz5660
Subject(s) - pulmonary hypertension , activin type 2 receptors , activin receptor , bmpr2 , medicine , acvr2b , bone morphogenetic protein , cardiology , endocrinology , tgf beta signaling pathway , biology , receptor , biochemistry , gene
Human genetics, biomarker, and animal studies implicate loss of function in bone morphogenetic protein (BMP) signaling and maladaptive transforming growth factor-β (TGFβ) signaling as drivers of pulmonary arterial hypertension (PAH). Although sharing common receptors and effectors with BMP/TGFβ, the function of activin and growth and differentiation factor (GDF) ligands in PAH are less well defined. Increased expression of GDF8, GDF11, and activin A was detected in lung lesions from humans with PAH and experimental rodent models of pulmonary hypertension (PH). ACTRIIA-Fc, a potent GDF8/11 and activin ligand trap, was used to test the roles of these ligands in animal and cellular models of PH. By blocking GDF8/11- and activin-mediated SMAD2/3 activation in vascular cells, ACTRIIA-Fc attenuated proliferation of pulmonary arterial smooth muscle cells and pulmonary microvascular endothelial cells. In several experimental models of PH, prophylactic administration of ACTRIIA-Fc markedly improved hemodynamics, right ventricular (RV) hypertrophy, RV function, and arteriolar remodeling. When administered after the establishment of hemodynamically severe PH in a vasculoproliferative model, ACTRIIA-Fc was more effective than vasodilator in attenuating PH and arteriolar remodeling. Potent antiremodeling effects of ACTRIIA-Fc were associated with inhibition of SMAD2/3 activation and downstream transcriptional activity, inhibition of proliferation, and enhancement of apoptosis in the vascular wall. ACTRIIA-Fc reveals an unexpectedly prominent role of GDF8, GDF11, and activin as drivers of pulmonary vascular disease and represents a therapeutic strategy for restoring the balance between SMAD1/5/9 and SMAD2/3 signaling in PAH.