Journal Article

Evaluation and Treatment of Endoplasmic Reticulum (ER) Stress in Right Ventricular Dysfunction during Monocrotaline-Induced Rat Pulmonary Arterial Hypertension

Kong, Hui, Zuo, Xiang-Rong, Zeng, Xiao-Ning, Xu, Jian, Wang, Jing-Jing, Xie, Wei-Ping, Cao, Quan, Zhou, Jin-Yong

2016

Overview

Purpose 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.

• Publisher: Springer US,Springer Nature B.V
• Subject: Activating Transcription Factor 6 - genetics / Activating Transcription Factor 6 - metabolism / Animals / Apoptosis - drug effects / Cardiology / eIF-2 Kinase - genetics / eIF-2 Kinase - metabolism / Endoplasmic Reticulum Stress - drug effects / Heart Ventricles - metabolism / Heart Ventricles - physiopathology / Heat-Shock Proteins - genetics / Heat-Shock Proteins - metabolism / Hypertension, Pulmonary - chemically induced / Hypertension, Pulmonary - drug therapy / Hypertension, Pulmonary - metabolism / Hypertension, Pulmonary - physiopathology / Male / Medicine / Medicine & Public Health / Membrane Proteins - genetics / Membrane Proteins - metabolism / Monocrotaline / Myocytes, Cardiac - drug effects / Myocytes, Cardiac - metabolism / Natriuretic Peptide, Brain - blood / Original Article / Peptide Fragments - blood / Phenylbutyrates - pharmacology / Phenylbutyrates - therapeutic use / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / Rats, Sprague-Dawley / RNA, Messenger - metabolism / Transcription Factor CHOP - genetics / Transcription Factor CHOP - metabolism / Ventricular Dysfunction, Right - chemically induced / Ventricular Dysfunction, Right - drug therapy / Ventricular Dysfunction, Right - metabolism / Ventricular Dysfunction, Right - physiopathology