Pérez-Carrillo Lorena, Giménez-Escamilla Isaac, García-Manzanares María, Triviño Juan Carlos, Feijóo-Bandín Sandra, Aragón-Herrera Alana, Lago Francisca, Martínez-Dolz Luis, Portolés Manuel, Tarazón Estefanía, Roselló-Lletí Esther
Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain.
Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain.
Antioxidants (Basel). 2023 Jun 24;12(7):1337. doi: 10.3390/antiox12071337.
Ischemic cardiomyopathy (ICM) is associated with abnormal microRNA expression levels that involve an altered gene expression profile. However, little is known about the underlying causes of microRNA disruption in ICM and whether microRNA maturation is compromised. Therefore, we focused on microRNA maturation defects analysis and the implication of the microRNA biogenesis pathway and redox-sensitive microRNAs (redoximiRs). Transcriptomic changes were investigated via ncRNA-seq (ICM, = 22; controls, = 8) and mRNA-seq (ICM, = 13; control, = 10). The effect of hypoxia on the biogenesis of microRNAs was evaluated in the AC16 cell line. ICM patients showed a reduction in microRNA maturation compared to control (4.30 ± 0.94 au vs. 5.34 ± 1.07 au, ˂ 0.05), accompanied by a deregulation of the microRNA biogenesis pathway: a decrease in pre-microRNA export (, FC = -1.38, ˂ 0.05) and cytoplasmic processing (, FC = -1.32, ˂ 0.01). Both processes were regulated by hypoxia in AC16 cells (, FC = -1.65; , FC = -1.55; ˂ 0.01; Exportin-5, FC = -1.81; Dicer, FC = -1.15; ˂ 0.05). Patients displayed deregulation of several redoximiRs, highlighting miR-122-5p (FC = -2.41, ˂ 0.001), which maintained a good correlation with the ejection fraction (r = 0.681, ˂ 0.01). We evidenced a decrease in microRNA maturation mainly linked to a decrease in XPO5-mediated pre-microRNA export and DICER1-mediated processing, together with a general effect of hypoxia through deregulation of biogenesis pathway and the redoximiRs.
缺血性心肌病（ICM）与涉及基因表达谱改变的异常微小RNA表达水平相关。然而，关于ICM中微小RNA破坏的潜在原因以及微小RNA成熟是否受损，人们了解甚少。因此，我们专注于微小RNA成熟缺陷分析以及微小RNA生物合成途径和氧化还原敏感微小RNA（redoximiRs）的影响。通过ncRNA测序（ICM，n = 22；对照组，n = 8）和mRNA测序（ICM，n = 13；对照组，n = 10）研究转录组变化。在AC16细胞系中评估缺氧对微小RNA生物合成的影响。与对照组相比，ICM患者的微小RNA成熟减少（4.30±0.94任意单位对5.34±1.07任意单位，P＜0.05），同时微小RNA生物合成途径失调：前体微小RNA输出减少（P，FC = -1.38，P＜0.05）和细胞质加工减少（P，FC = -1.32，P＜0.01）。在AC16细胞中，这两个过程均受缺氧调节（P，FC = -1.65；P，FC = -1.55；P＜0.01；Exportin-5，FC = -1.81；Dicer，FC = -1.15；P＜0.05）。患者表现出几种redoximiRs失调，突出显示miR-122-5p（FC = -2.41，P＜0.001），其与射血分数保持良好相关性（r = 0.681，P＜0.01）。我们证明微小RNA成熟减少主要与XPO5介导的前体微小RNA输出和DICER1介导的加工减少有关，同时缺氧通过生物合成途径和redoximiRs失调产生总体影响。
