title: Evaluation and Treatment of Endoplasmic Reticulum (ER) Stress in Right Ventricular Dysfunction during Monocrotaline-Induced Rat Pulmonary Arterial Hypertension.
abstract: OBJECTIVE
  Endoplasmic reticulum (ER) stress contributes to pulmonary artery hypertension (PAH). However, the exact roles of ER stress in right ventricular (RV) dysfunction, which is strongly associated with PAH, are largely unknown. Here, we aimed to explore how ER stress affects RV function in a rat PAH model and evaluated the effects of an ER stress inhibitor on RV dysfunction.
  
  
  METHODS
  We examined expression changes of an ER marker: chaperone glucose-regulated protein 78 (GRP78), three ER stress sensor proteins: activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1), and protein kinase RNA-like endoplasmic reticulum kinase (PERK), and a key ER stress-induced apoptosis indicator: CCAAT/enhancer-binding protein homologous protein (CHOP), with inflammation indicators: interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and matrix metalloproteinases (MMPs) in RV at 3, 7, 14 and 28 days following a single dose of monocrotaline (MCT) injection, with or without a preventive treatment [4-phenylbutyric acid (PBA)]. RV function was evaluated by histological, molecular and echocardiographic analysis.
  
  
  RESULTS
  1) GRP78 protein expression started to increase (1.5 ± 0.06 fold change) at 3d post MCT injection, even before the formation of PAH. 2) ATF6, IRE1, and PERK showed distinctive expression patterns post MCT injection. 3) CHOP expression remained low at day 3 & 7, but significantly increased at day 14 (p < 0.05), along with the peak of RV cardiomyocytes apoptosis. 4) PBA inhibited ER stress and alleviated remodeling and dysfunction in the RV.
  
  
  CONCLUSIONS
  The early phase of ER stress might benefit RV function, whereas the extended phase led to RV cardiomyocyte apoptosis and dysfunction. Inhibition of ER stress by PBA during PAH directly improved RV function.
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Department of Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Xiang-Rong
authors.initials: XR
authors.lastname: Zuo
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Central Laboratory, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Jin-Yong
authors.initials: JY
authors.lastname: Zhou
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Kong
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Zeng
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China. xieweiping.njmu@gmail.com.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Xie
authors.affiliation: Department of Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Cao
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016686:Monocrotaline; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D010654:Phenylbutyrates / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051702:Activating Transcription Factor 6; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D016686:Monocrotaline; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D010654:Phenylbutyrates; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497113:Atf6 protein, rat; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C109794:pro-brain natriuretic peptide (1-76); C075773:4-phenylbutyric acid; C486557:Ern2 protein, rat
keywords: Apoptosis; Endoplasmic reticulum (ER) stress; Inflammation; Pulmonary artery hypertension; Right ventricular dysfunction