TY - JOUR
T1 - ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension
AU - Yung, Lai Ming
AU - Yang, Peiran
AU - Joshi, Sachindra
AU - Augur, Zachary M.
AU - Kim, Stephanie S.J.
AU - Bocobo, Geoffrey A.
AU - Dinter, Teresa
AU - Troncone, Luca
AU - Chen, Po Sheng
AU - McNeil, Megan E.
AU - Southwood, Mark
AU - de Frias, Sergio Poli
AU - Knopf, John
AU - Rosas, Ivan O.
AU - Sako, Dianne
AU - Scott Pearsall, R.
AU - Quisel, John D.
AU - Li, Gang
AU - Kumar, Ravindra
AU - Yu, Paul B.
N1 - Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
PY - 2020/5/13
Y1 - 2020/5/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85084627578&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85084627578&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aaz5660
DO - 10.1126/scitranslmed.aaz5660
M3 - Article
C2 - 32404506
AN - SCOPUS:85084627578
SN - 1946-6234
VL - 12
JO - Science translational medicine
JF - Science translational medicine
IS - 543
M1 - aaz5660
ER -