Prognostic significance of circulating level of GRP78 in pulmonary arterial hypertension

BACKGROUND: Endoplasmic reticulum (ER) stress is associated with pulmonary arterial hypertension (PAH), and glucose-regulated protein 78 (GRP78) is an important marker of ER stress in PAH. Most studies have shown that its expression is increased at both lung and right ventricle as well as pulmonary vascular cells during ER stress. Currently, circulating GRP78 levels are also shown to be significantly increased in several diseases and can be used as a disease biomarker. METHODS: Culture media from pulmonary artery smooth muscle cells (PASMCs) and cardiomyocytes with different trigger interventions were collected. Plasma was harvested from control, monocrotaline (MCT)-treated and Sugen-hypoxia (SuHx) treated rats. Plasma was also collected from 66 PAH patients and 40 healthy controls. GRP78 levels were measured by ELISA. RESULTS: The extracellular GRP78 levels were significantly increased in hypoxia-treated PASMCs and cardiomyocytes compared with the normoxia group. Circulating levels of GRP78 were significantly increased in the MCT and SuHx groups compared with the control group. Circulating GRP78 levels are higher in PAH patients. In subgroup analyses, GRP78 was higher in the Idiopathic PAH (IPAH), Congenital heart disease-associated PAH (CHD-PAH), world heart World Health Organization Function Class (WHO-FC) III/IV, and intermediate-high-risk groups. COX regression analysis (hazard ratio, HR) and Kaplan-Meier survival analysis showed that GRP78 was a prognostic risk factor for event-free survival (HR 1.422 per 1 µg/mL, 95% CI 1.188–1.702). CONCLUSION: In PAH, circulating GRP78 is significantly elevated and serves as an incremental prognostic biomarker for event-free survival.