PERK-Mediated Suppression of microRNAs by Sildenafil Improves Mitochondrial Dysfunction in Heart Failure
PERK-Mediated Suppression of microRNAs by Sildenafil Improves Mitochondrial Dysfunction in Heart Failure
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DOI：
10.1016/j.isci.2020.101410
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发表时间：
2020-08-21
期刊：
影响因子：
5.8
通讯作者：
Wada, Youichiro
中科院分区：
文献类型：
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作者：
Shimizu, Takashi;Taguchi, Akashi;Wada, Youichiro
氧化/亚硝化应激是心脏功能障碍的主要触发因素，涉及未折叠蛋白反应和线粒体功能障碍。西地那非激活一氧化氮-环磷酸鸟苷-蛋白激酶G信号通路可改善压力超负荷所致心力衰竭时心脏重构的不良反应。在使用或不使用西地那非治疗的衰竭心脏中进行了转录组分析。蛋白激酶R样内质网(ER)激酶(PERK)Dowistream信号通路eIF2和NRF2明显改变。虽然eIF2信号被抑制，但NRF2信号被上调，通过EGFR介导的Ago2磷酸化抑制miR 24-3p的成熟。为了研究西地那非对这些途径的影响，我们培育了心脏特异性PERK基因敲除小鼠。在这些小鼠中，西地那非不能抑制成熟，抑制NRF2的核转位，并加剧线粒体功能障碍。综上所述，这些结果表明，西地那非通过PERK介导的miRNAs抑制对于通过NRF2介导的氧化应激反应维持线粒体的动态平衡至关重要。
Oxidative/nitrosative stress is a major trigger of cardiac dysfunction, involving the unfolded protein response and mitochondrial dysfunction. Activation of nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling by sildenafil improves cardiac mal-remodeling during pressure-overload-induced heart failure. Transcriptome analysis was conducted in failing hearts with or without sildenafil treatment. Protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) dowistream signaling pathways, EIF2 and NRF2, were significantly altered. Although EIF2 signaling was suppressed, NRF2 signaling was upregulated, inhibiting the maturation of miR 24-3p through EGFR-mediated Ago2 phosphorylation. To study the effect of sildenafil on these pathmays, we generated cardiac-specific PERK knockout mice. In these mice, sildenafil could not inhibit the maturations, the nuclear translocation of NRF2 was suppressed, and mitochondrial dysfunction advanced. Altogether, these results show that PERK-mediated suppression of miRNAs by sildenafil is vital for maintaining mitochondrial homeostasis through NRF2-mediated oxidative stress response.