Use of protein chaperones to correct BMP receptor processing errors in Hereditary Pulmonary Arterial Hypertension

Abstract

Patients with HPAH inherit heterozygous mutations in the Bone Morphogenetic Type 2 receptor (BMPR2). BMPR2 mutations subject to non‐sense mediated mRNA decay (NMD+) promote less severe pulmonary hypertension (PH) than BMPR2 mutations that escape NMD (NMD‐). Moreover, we have shown that mice carrying the NMD+ Bmpr2 mutation, Bmpr2+/−, are less susceptible to PH than mice carrying the NMD‐ Bmpr2Δex2/+mutation. To explore the mechanisms underlying these differences we evaluated expression of mutant receptor products in isolated pulmonary endothelial cells (PECs). PECs from Bmpr2Δex2/+ mice express the 150kDa wild type Bmpr2 protein product, but also express high levels of a 125kDa product that is also seen in skin fibroblasts from HPAH patients with the same BMPR2 ΔEXON2 mutation. Biochemical studies indicate that this endogenous Bmpr2Δex2 product is retained in the ER, and that BMP‐dependent Smad 1/5/8 signaling is reduced in Bmpr2Δex2/+ PECs. Moreover, treatment with chemical chaperones restores cell surface expression of Bmpr2Δex2 and rescues the BMP signaling defects in these cells. These rescue studies suggest that protein chaperones can be used to correct BMP signaling defects in HPAH patients and mice with NMD‐ BMPR2 mutations. We are currently testing this hypothesis by determining whether the chemical chaperone 4PBA also reduces susceptibility of Bmpr2Δex2/+ mice to PH in vivo.