下调和上调
内质网
未折叠蛋白反应
收缩性
细胞生物学
医学
衣霉素
平衡
基因敲除
内科学
内分泌学
生物
细胞凋亡
生物化学
基因
作者
Luíz Henrique Marchesi Bozi,Ana Paula Cremasco Takano,Juliane C. Campos,Natale Rolim,Paulo Magno Martins Dourado,Vanessa Azevedo Voltarelli,Ulrik Wisløff,Julio Cesar Batista Ferreira,Maria Luíza Morais Barreto‐Chaves,Patrícia Chakur Brum
标识
DOI:10.1016/j.ijcard.2018.08.070
摘要
Disruption of endoplasmic reticulum (ER) homeostasis is a common feature of cardiac diseases. However, the signaling events involved in ER stress-induced cardiac dysfunction are still elusive. Here, we uncovered a mechanism by which disruption of ER homeostasis impairs cardiac contractility.We found that ER stress is associated with activation of JNK and upregulation of BNIP3 in a post-myocardial infarction (MI) model of cardiac dysfunction. Of interest, 4-week treatment of MI rats with the chemical ER chaperone 4-phenylbutyrate (4PBA) prevented both activation of JNK and upregulation of BNIP3, and improved cardiac contractility. We showed that disruption of ER homeostasis by treating adult rat cardiomyocytes in culture with tunicamycin leads to contractile dysfunction through JNK signaling pathway. Upon ER stress JNK upregulates BNIP3 in a FOXO3a-dependent manner. Further supporting a BNIP3 mechanism for ER stress-induced deterioration of cardiac function, siRNA-mediated BNIP3 knockdown mitigated ER stress-induced cardiomyocyte dysfunction by reestablishing sarcoplasmic reticulum Ca2+ content.Collectively, our data identify JNK-dependent upregulation of BNIP3 as a critical process involved in ER stress-induced cardiomyocyte contractile dysfunction and highlight 4PBA as a potential intervention to counteract ER stress-mediated BNIP3 upregulation in failing hearts.
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