ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension

Lai Ming Yung, Peiran Yang, Sachindra Joshi, Zachary M. Augur, Stephanie S.J. Kim, Geoffrey A. Bocobo, Teresa Dinter, Luca Troncone, Po Sheng Chen, Megan E. McNeil, Mark Southwood, Sergio Poli de Frias, John Knopf, Ivan O. Rosas, Dianne Sako, R. Scott Pearsall, John D. Quisel, Gang Li, Ravindra Kumar, Paul B. Yu

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Abstract

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.

Original languageEnglish
JournalScience translational medicine
Volume12
Issue number543
DOIs
Publication statusPublished - 2020 May 13

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Yung, L. M., Yang, P., Joshi, S., Augur, Z. M., Kim, S. S. J., Bocobo, G. A., Dinter, T., Troncone, L., Chen, P. S., McNeil, M. E., Southwood, M., Poli de Frias, S., Knopf, J., Rosas, I. O., Sako, D., Pearsall, R. S., Quisel, J. D., Li, G., Kumar, R., & Yu, P. B. (2020). ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension. Science translational medicine, 12(543). https://doi.org/10.1126/scitranslmed.aaz5660