Introduction:

Pulmonary arterial hypertension (PAH) is driven by vascular remodelling due to inflammation and cellular stress, including endoplasmic reticulum stress (ER stress). The main ER-stress chaperone, glucose-regulated protein 78 kDa (GRP78), is known to have protective effects in inflammatory diseases through extracellular signalling. The aim of this study is to investigate its significance in PAH.

Methods and Results:

Pulmonary arterial smooth muscle cells (PASMC) were stimulated with compounds that induce ER stress (Tunicamycin and thapsigargin), after which the secretion of GRP78 into the cell medium was analysed by western blot. Next, naïve PASMC were treated with conditioned medium (CM) from the ER-stressed donor PASMC. In vitro, we found that when ER stress was induced in PASMC, there was also a time-dependent extracellular secretion of GRP78. Incubation with CM from ER-stressed PASMC reduced the viability, oxidative stress and expression of inflammatory (NFkB, IL-6) and ER-stress markers (GRP78, CHOP) in target cells. These effects were abrogated when the donor cells were co-treated with Brefeldin A to inhibit active secretion of GRP78. Direct treatment of PASMC with recombinant GRP78 modulated the expression of key inflammatory markers. Additionally, we measured GRP78 plasma levels in 19 PAH patients (Nice Group I) and correlated the levels to risk stratification according to ESC guidelines. In PAH patients, elevated plasma levels of GRP78 were associated with a favourable risk stratification. 

Conclusion:

In conclusion, GRP78 is secreted by PASMC under ER stress and exhibits protective effects from the hallmarks of PAH in vitro. Circulating GRP78 may serve as biomarker for risk adjudication of patients with PAH.