Abstract
Background
Endoplasmic reticulum (ER) stress plays an important role in mediating ischemic heart
cell death. The aim of this study was to investigate whether manipulation of a key
factor of the ER stress pathway, eukaryotic translation initiation factor 2 subunit
α (eIF2α), can change the natural history of heart failure (HF).
Methods
HF was induced using coronary artery ligation in adult rats and a selective eIF2α
dephosphorylation inhibitor, salubrinal (Sal), was used. Thirty minutes after ligation,
rats were randomly assigned to 3 groups: myocardial infarction (MI) plus placebo injections
(dimethyl sulfoxide; n = 12), MI plus Sal injection (Sal; n = 12), and MI (HF; n =
12). Hemodynamic parameters were examined. Hearts were harvested for apoptosis assessment
after 8 weeks of Sal treatment by terminal deoxynucleotidyl transferase deoxyuridine
triphosphate nick end labelling and flow cytometric analysis. Hearts were harvested
to determine ER chaperones by Western analysis, real-time polymerase chain reaction
and immunohistochemical analysis.
Results
Cardiac function was significantly improved in Sal-treated rats. Apoptosis was reduced
by Sal treatment. Glucose-regulated protein-78 and -94 were increased in HF but normalized
by Sal treatment. HF caused a significant increase in eIF2α phosphorylation, which
was further increased by Sal treatment, and caspase-12 and phospho-c-JUN NH2-terminal kinase were markedly increased in rats with HF alone but significantly reduced
by Sal treatment.
Conclusions
Our results suggest that reduction of ER stress and myocardial apoptosis through inhibition
of eIF2α dephosphorylation might alter the natural history of HF, which might provide
a new approach for its treatment.
Résumé
Introduction
Le stress du réticulum endoplasmique (RE) joue un rôle important de médiation de la
mort des cellules cardiaques lors de l’ischémie. Le but de cette étude était d’examiner
si la manipulation d’un facteur principal de la voie du stress du RE, la sous-unité
α du facteur d’initiation de la traduction eucaryote 2 (eIF2α), peut changer l’évolution
naturelle de l’insuffisance cardiaque (IC).
Méthodes
L’IC a été induite par la ligature de l’artère coronaire chez des rats adultes, et
un inhibiteur sélectif de la déphosphorylation du eIF2α, le salubrinal (Sal), a été
utilisé. Trente (30) minutes après la ligature, les rats ont été répartis de manière
aléatoire en 3 groupes : l’infarctus du myocarde (IM) plus les injections de placébo
(diméthylsulfoxyde; n = 12), l’IM plus l’injection de Sal (Sal; n = 12) et l’IM (IC;
n = 12). Les paramètres hémodynamiques ont été examinés. Les cœurs ont été prélevés
pour procéder à l'évaluation de l'apoptose après 8 semaines de traitements au Sal
par le marquage de la cassure d'un brin d'extrémité à la déoxyuridine triphosphate
et l'analyse de cytométrie de flux. Les cœurs ont été prélevés et les chaperonnes
du RE ont été déterminées par l’analyse du buvardage de western, la réaction en chaîne
de la polymérase en temps réel et l’analyse immunohistochimique.
Résultats
La fonction cardiaque a été améliorée de façon significative chez les rats traités
au Sal. L’apoptose a été réduite par le traitement au Sal. Les protéines 78 et 94
régulées par le glucose ont augmenté lors de l’IC, mais se sont normalisées à la suite
du traitement au Sal. L’IC a causé une augmentation significative de la phosphorylation
du eIF2α, qui a été davantage accrue par le traitement au Sal, puis la caspase 12
et la protéine JNK ont nettement augmenté chez les rats ayant une IC seule, mais ont
significativement été réduites à la suite du traitement au Sal.
Conclusions
Nos résultats montrent que la réduction du stress du RE et de l’apoptose myocardique
par l’inhibition de la déphosphorylation du eIF2α modifierait l’évolution naturelle
de l’IC, ce qui offrirait une nouvelle approche pour son traitement.
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Article info
Publication history
Published online: November 08, 2013
Accepted:
December 8,
2013
Received:
November 14,
2013
Footnotes
See page 374 for disclosure information.
Identification
Copyright
© 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
