4pba restores signaling of a cysteine-substituted mutant bmpr2 receptor found in patients with pulmonary arterial hypertension

Dunmore, Benjamin J., Yang, Xu Dong, Crosby, Alexi, Moore, Stephen, Long, Lu, Huang, Christopher, Southwood, Mark, Austin, Eric D., Rana, Amer ORCID: https://orcid.org/0000-0002-2330-4643, Upton, Paul D. and Morrell, Nicholas W. (2020) 4pba restores signaling of a cysteine-substituted mutant bmpr2 receptor found in patients with pulmonary arterial hypertension. American Journal of Respiratory Cell and Molecular Biology, 63 (2). pp. 160-171. ISSN 1044-1549

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Mutations in the gene encoding BMPR2 (bone morphogenetic protein type 2 receptor) are the major cause of heritable pulmonary arterial hypertension (PAH). Point mutations in the BMPR2 ligandbinding domain involving cysteine residues (such as C118W) are causative of PAH and predicted to cause protein misfolding. Using heterologous overexpression systems, we showed previously that these mutations lead to retention of BMPR2 in the endoplasmic reticulum but are partially rescued by chemical chaperones. Here, we sought to determine whether the chemical chaperone 4-phenylbutyrate (4PBA) restores BMPR2 signaling in primary cells and in a knockin mouse harboring a C118W mutation. First, we confirmed dysfunctional BMP signaling in dermal fibroblasts isolated from a family with PAH segregating the BMPR2 C118W mutation. After BMP4 treatment, the induction of downstream signaling targets (Smad1/5, ID1 [inhibitor of DNA binding 1], and ID2) was significantly reduced in C118W mutant cells. Treatment with 4PBA significantly rescued Smad1/5, ID1, and ID2 expression. Pulmonary artery smooth muscle cells isolated from the lungs of heterozygous mice harboring the Bmpr2 C118W mutation exhibited significantly increased proliferation. In the presence of 4PBA, hyperproliferation was dramatically reduced. Furthermore, in vivo, 4PBA treatment of Bmpr2 C118W mice partially rescued Bmpr2 expression, restored downstream signaling, and improved vascular remodeling. These findings demonstrate in primary cells and in a knockin mouse that the repurposed small-molecule chemical chaperone 4PBA might be a promising precision medicine approach to treat PAH in patients with specific subtypes of BMPR2 mutation involving cysteine substitutions in the ligand-binding domain.

Item Type: Article
Additional Information: Funding Information: Supported by the British Heart Foundation (B.J.D., X.Y., A.C., S.M., and P.D.U.), British Heart Foundation program grant RG/13/4/30107 (N.W.M.), and the Fondation Leducq (N.W.M.). Infrastructure support was provided by the Cambridge National Institute for Health Research Biomedical Research Center. Publisher Copyright: © 2020 by the American Thoracic Society.
Uncontrolled Keywords: hypertension,mutation,pulmonary,treatment,molecular biology,pulmonary and respiratory medicine,clinical biochemistry,cell biology ,/dk/atira/pure/subjectarea/asjc/1300/1312
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 01 Nov 2022 14:31
Last Modified: 01 Nov 2022 14:31
URI: https://ueaeprints.uea.ac.uk/id/eprint/89464
DOI: 10.1165/rcmb.2019-0321OC

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