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

被引:62
作者
Liu, Yu [1 ,2 ]
Wang, Jie [3 ]
Qi, Shu-Ying [1 ]
Ru, Lei-Sheng [1 ]
Ding, Chao [1 ]
Wang, Hai-Jun [4 ]
Zhao, Jing-Shan [2 ]
Li, Jing-Jing [1 ]
Li, Ai-ying [2 ]
Wang, Dong-Mei [1 ]
机构
[1] Peace Hosp PLA, Dept Cardiol, Shijiazhuang 050082, Hebei, Peoples R China
[2] Hebei Tradit Chinese Med Coll, Sch Basic Med, Dept Biochem & Mol Biol, Lab Med Biotechnol Hebei Prov, Shijiazhuang, Hebei, Peoples R China
[3] Columbia Univ, Coll Phys & Surg, Dept Med, Div Cardiol, New York, NY USA
[4] Hebei Med Univ, Affiliated Hosp 4, Dept Surg, Shijiazhuang, Hebei, Peoples R China
关键词
UNFOLDED PROTEIN RESPONSE; ER STRESS; APOPTOSIS; CELLS; DISEASE; BETA; ACTIVATION; INITIATION; DEATH; INHIBITION;
D O I
10.1016/j.cjca.2013.11.001
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
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 alpha (eIF2 alpha), can change the natural history of heart failure (HF). Methods: HF was induced using coronary artery ligation in adult rats and a selective eIF2 alpha 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 eIF2 alpha 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 eIF2 alpha dephosphorylation might alter the natural history of HF, which might provide a new approach for its treatment.
引用
收藏
页码:368 / 375
页数:8
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