Document Detail

Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension.
MedLine Citation:
PMID:  24610918     Owner:  NLM     Status:  Publisher    
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 (RVSP) 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 RVSP 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 ATF6 branch, sXbp1 and Pdi in the IRE1 branch and Atf4 in the PERK branch, and reduced phosphorylation of JNK and eIF2α 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 (PASMC) by chronic stimulation of PDGF-BB or hypoxia. Furthermore, knockdown of each UPR branch sensor activated other branches and promoted proliferation of PASMC. 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.
Masayuki Koyama; Masato Furuhashi; Shutaro Ishimura; Tomohiro Mita; Takahiro Fuseya; Yusuke Okazaki; Hideaki Yoshida; Kazufumi Tsuchihashi; Tetsuji Miura
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-3-7
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  -     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2014 Mar 
Date Detail:
Created Date:  2014-3-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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