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 - Funding Information:
We thank N. Morrell, M.-J. Goumans, and P. ten Dijke for critical feedback and R. Machado Rezende and A. Miller for technical help. This work was supported by the U.S. NIH (HL131910, HL132742, and AR057374 to P.B.Y.), a Gilead Sciences Research Scholars Program award in PAH (to L.-M.Y.), an AHA Career Development Award (to L.-M.Y.), a Leducq Foundation Transatlantic Network of Excellence Award (to P.B.Y.), and a research gift from Acceleron Pharma Inc. (to P.B.Y.).
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
VL - 12
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 543
M1 - aaz5660
ER -