Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and
vascular remodeling of the pulmonary artery (PA). Recently, endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) have been disclosed in various types of diseases. Here we examined whether ER stress is involved in the pathogenesis of PAH. Four weeks of chronic normobaric
hypoxia increased right ventricular (RV) systolic pressure by 63% compared with that in normoxic controls and induced RV
hypertrophy and medial thickening of the PA in C57BL/6J mice. Treatment with
4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced RV systolic pressure by 30%, attenuated RV
hypertrophy and PA muscularization, and increased total running distance in a treadmill test by 70% in hypoxic mice. The beneficial effects of
4-PBA were associated with suppressed expression of inflammatory
cytokines and ER stress markers, including
Grp78 and
Grp94 in the activating transcription factor-6 branch, sXbp1 and Pdi in the
inositol-requiring enzyme-1 branch and Atf4 in the PKR-like ER
kinase branch, and reduced phosphorylation of c-Jun NH2-terminal
kinase and eukaryotic translation initiation factor-2α in the lung. The pattern of changes in ER stress and inflammatory markers by
4-PBA in the lung of the PAH model was reproduced in PA smooth muscle cells by chronic stimulation of
platelet-derived growth factor-BB or
hypoxia. Furthermore, knockdown of each UPR branch sensor activated other branches and promoted proliferation of PA smooth muscle cells. The findings indicate that activation of all branches of the UPR and accompanying
inflammation play a major role in the pathogenesis of PAH, and that chemical chaperones are potentially therapeutic agents for PAH.