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Canadian Journal of Cardiology

Reduced Endoplasmic Reticulum Stress Might Alter the Course of Heart Failure Via Caspase-12 and JNK Pathways

Published:November 08, 2013DOI:https://doi.org/10.1016/j.cjca.2013.11.001

      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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