Ischemic dilated cardiomyopathy pathophysiology through microRNA-16-5p
Ischemic dilated cardiomyopathy pathophysiology through microRNA-16-5p
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DOI：
10.1016/j.rec.2020.08.012
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发表时间：
2021-09-01
影响因子：
5.9
通讯作者：
Toro, Rocio
中科院分区：
文献类型：
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作者：
Calderon-Dominguez, Maria;Mangas, Alipio;Toro, Rocio
引言和目的microRNA-16- 5 p（miR-16）的表达水平在缺血性心肌病和缺血性扩张型心肌病（iDCM）动物模型中上调，诱导心肌细胞凋亡。我们研究了miR-16在凋亡iDCM环境中与内质网（ER）应激和自噬相关的适应性细胞反应中的作用。我们定量了168名参与者的miR-16血浆水平-76名对照，60名iDCM患者，和32例家族性扩张型心肌病患者的BAG 3-通过定量真实的-时间聚合酶链反应，并与患者变量的水平。在人心脏细胞系中分析了细胞内miR-16过表达的影响。测定细胞凋亡和细胞活力，以及与ER应激、心脏损伤和自噬相关的标志物水平。结果：iDCM患者血浆miR-16水平上调（P = .039）。多变量逻辑回归模型确定了miR-16与iDCM临床变量的相关性（P < .001）。在体外，miR-16过表达增加细胞凋亡（P = .02），降低细胞活力（P = .008）。此外，它诱导ER应激的促凋亡成分，基于PERK/CHOP通路的上调。然而，我们观察到自噬流量的增加（P <0.001），而不是溶酶体阻断miR 16作为一种可能的细胞保护机制。在缺血环境中，miR-16激活ER应激并促进炎症，随后在人类心脏细胞中发生自噬。因此，自噬可能是一种尝试，以维持细胞的稳态响应错误折叠/聚集的蛋白质相关的ER应激，细胞凋亡之前。(C)2020年西班牙心脏病学会。出版社：Elsevier Espana，S.L.U. All rights reserved.
Introduction and objectives The expression levels of microRNA-16-5p (miR-16) are upregulated in ischemic cardiomyopathy and in animal models of ischemic dilated cardiomyopathy (iDCM), inducing myocardial apoptosis. We investigated the role of miR-16 in the adaptive cellular response associated with endoplasmic reticulum (ER) stress and autophagy in the apoptotic iDCM environment.Methods: We quantified the miR-16 plasma levels of 168 participants-76 controls, 60 iDCM patients, and 32 familial DCM patients with the pathogenic variant of BAG3-by quantitative real-time polymerase chain reaction and correlated the levels with patient variables. The effects of intracellular miR-16 overexpression were analyzed in a human cardiac cell line. Apoptosis and cell viability were measured, as well as the levels of markers associated with ER stress, cardiac injury, and autophagy.Results: Plasma miR-16 levels were upregulated in iDCM patients (P = .039). A multivariate logistic regression model determined the association of miR-16 with iDCM clinical variables (P < .001). In vitro, miR-16 overexpression increased apoptosis (P = .02) and reduced cell viability (P = .008). Furthermore, it induced proapoptotic components of ER stress, based on upregulation of the PERK/CHOP pathway. However, we observed augmentation of autophagic flux (P < .001) without lysosomal blockade by miR16 as a possible cytoprotective mechanism.Conclusion: MiR-16 is specifically associated with iDCM. In an ischemic setting, miR-16 activates ER stress and promotes inflammation followed by autophagy in human cardiac cells. Thus, autophagy may be an attempt to maintain cellular homeostasis in response to misfolded/aggregated proteins related to ER stress, prior to apoptosis. (C) 2020 Sociedad Espanola de Cardiologfa. Published by Elsevier Espana, S.L.U. All rights reserved.