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

半胱氨酸蛋白酶12 医学 未折叠蛋白反应 内质网 脱磷 细胞凋亡 内科学 内分泌学 心力衰竭 末端脱氧核苷酸转移酶 程序性细胞死亡 磷酸化 标记法 半胱氨酸蛋白酶 细胞生物学 磷酸酶 生物 生物化学 免疫组织化学
作者
Yu Liu,Jie Wang,Shu-Ying Qi,Lei-sheng Ru,Chao Ding,Haijun Wang,Jingshan Zhao,Jingjing Li,Aiying Li,Xinran Ma
出处
期刊:Canadian Journal of Cardiology [Elsevier]
卷期号:30 (3): 368-375 被引量:40
标识
DOI:10.1016/j.cjca.2013.11.001
摘要

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.
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