4PBA Restores Signalling of a Cysteine-substituted Mutant BMPR2 Receptor Found in Patients with PAH.

4PBA Restores Signalling of a Cysteine-substituted Mutant BMPR2 Receptor Found in Patients with PAH. Am J Respir Cell Mol Biol. 2020 Apr 07;: Authors: Dunmore BJ, Yang X, Crosby A, Moore S, Long L, Huang C, Southwood M, Austin ED, Rana A, Upton PD, Morrell NW Abstract Mutations in the gene encoding the bone morphogenetic protein type 2 receptor, BMPR2, are the major cause of heritable pulmonary arterial hypertension (HPAH). Point mutations in the BMPR2 ligand binding 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 determine whether the chemical chaperone, 4-PBA, restores BMPR2 signalling in primary cells and in a knock-in mouse harbouring a C118W mutation. First, we confirmed dysfunctional BMP signalling in dermal fibroblasts isolated from a PAH family segregating the BMPR2 C118W mutation. Following BMP4 treatment, the induction of downstream signalling targets, Smad1/5, ID1 and ID2, was significantly reduced in C118W mutant cells. Treatment with 4-PBA significantly rescued Smad1/5, ID1 and ID2 expression. Pulmonary artery smooth muscle cells (PASMCs) isolated from the lungs of heterozygous mice harbouring the Bmpr2 C118W mutation exhibited significantly increased prolife...
Source: Am J Respir Cell Mol... - Category: Respiratory Medicine Authors: Tags: Am J Respir Cell Mol Biol Source Type: research