Abstract 12957: Endoplasmic Reticulum Stress in Pulmonary Artery Smooth Muscle Cells Contributes to the Development of Pulmonary Hypertension Induced by Chronic Hypoxia
Background: Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction, and vascular remodeling in the pulmonary vasculature, and its pathogenesis involves platelet-derived growth factor (PDGF) signaling. The endoplasmic reticulum (ER) stress is a predominant feature in several types of diseases, including proliferative diseases. However, little is known about the link between ER stress and PAH. In this study, we examined whether ER stress is involved in the development of PAH induced by chronic hypoxia.
Methods and Results: PAH, right ventricular (RV) hypertrophy, thickening of pulmonary artery (PA) media and exercise intolerance were induced in C57BL/6J mice by 4-week chronic normobaric hypoxia. Treatment with 4-phenylbutyric acid (4-PBA), an ER stress modulator, commencing at the onset of hypoxia significantly attenuated PAH, RV hypertrophy and PA muscularization and improved exercise tolerance. These beneficial effects of 4-PBA were associated with suppressed gene expressions of glucose-regulated protein 78 (Grp78), Grp94, spliced X box-binding protein 1 (sXbp1), protein disulfide isomerase (Pdi), and activating transcription factor 4 (Atf4) and reduced phosphorylation of c-Jun N-terminal kinase (JNK) and eukaryotic translation initiation factor 2α (eIF2 α) in the lung. The pattern of the changes in the unfolded protein response signaling molecules in the lung of PAH mice were mimicked in PA smooth muscle cells (PASMCs) in vitro by chronic hypoxia and by treatment with PDGF. Furthermore, treatment with 4-PBA suppressed PDGF-induced proliferation and expressions of pro-inflammatory cytokines in PASMCs.
Conclusion: Our findings indicate that ER stress plays a major role in pathogenesis in PAH downstream of PDGF signaling and that chemical chaperones are potentially therapeutic agents for treatment of PAH.
- © 2013 by American Heart Association, Inc.