miR-181a通过调控醛固酮-盐皮质激素受体通路参与心脏重塑
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miR-181a通过调控醛固酮-盐皮质激素受体通路参与心脏重塑
翻译：唐剑 编辑：冯玉蓉 审校：曹莹
背景：醛固酮-肾上腺皮质激素受体（Aldo-MR）通路在心脏应激期间被激活，如高血压、心肌梗死（MI）和心力衰竭等。Aldo和MR在心脏病发病机制中的重要性已被充分证实；然而，Aldo/MR引起的心脏重塑背后的调控机制仍不清楚。为了进一步研究其机制，我们探讨了miRNA介导的Aldo-MR通路的潜在调控机制。
方法和结果：用MR反应稳定的心肌细胞系(MMTV-GFP-HL-1)对2555个miRNA进行高通量筛选，发现miR-181a是Aldo-MR通路的潜在调节因子。发现miR-181a下调了Aldo-MR下游效应分子Ngal（脂质运载蛋白2）的表达。此外，miR-181a过表达后，Aldo诱导的心肌细胞肥大明显减少。在小鼠MI模型中，基因敲除miR-181a可导致心功能恶化、心脏重塑和Aldo-MR通路激活，而AAV9介导的miR-181a过表达改善了心功能，并使Aldo-MR通路失活，证明miR-181a具有心脏保护作用。对Aldo处理的miR-181a过表达/不过表达的细胞进行全部RNA测序，发现在Aldo-MR通路中发挥功能的miR-181a潜在作用靶点。我们发现，作为miR-181a的直接作用靶点，Adamts1在miR-181a过表达时下调，在miR-181a抑制时上调。与miR-181a过表达相似，siRNA介导的Adamts1抑制作用也抑制了Aldo-MR通路。
结论：研究表明，miR-181a是Aldo-MR通路的一种新的调节因子，可通过直接靶向作用于Adamts1调节Ngal的水平。这一新见解将miR-181a确立为参与Aldo-MR通路下游网络的重要因素。我们的在体研究进一步证实了miR-181a在MI应激下具有心脏保护作用。因此，miR-181a参与Aldo-MR介导的心脏重塑，可能成为新的治疗靶点。
文献来源：Ankita Garg1, Ariana Foinquinos1, Mira Jung, et al. MiRNA-181a is a novel regulator of aldosterone mineralocorticoid receptor-mediated cardiac remodelling.Eur J Heart Fail 2020 Apr 18.
MiRNA-181a is a novel regulator of aldosterone-mineralocorticoid receptor-mediated cardiac remodelling
Abstract
AIM: The aldosterone-mineralocorticoid receptor (Aldo-MR) pathway is activated during cardiac stress, such as hypertension, myocardial infarction (MI), and heart failure. The importance of Aldo and MR in the pathogenesis of cardiac diseases is well established; however, the regulatory mechanisms behind Aldo/MR-induced cardiac remodelling remain uncertain. We here investigated potential miRNA-mediated regulation of the Aldo-MR pathway to improve mechanistic understanding.
METHODS AND RESULTS: High-throughput screening of 2,555 miRNAs using an MR responsive stable cardiomyocyte cell line (MMTV-GFP-HL-1) identified miR-181a as a potential regulator of Aldo-MR pathway. MiR-181a was found to downregulate the expression of Ngal (lipocalin-2), a well-established downstream effector molecule of Aldo-MR. In addition, Aldo-induced cellular hypertrophy decreased significantly upon miR-181a overexpression. Genetic miR-181 knockout in murine MI model led to deteriorated cardiac function, cardiac remodelling, and activation of Aldo-MR pathway while AAV9-mediated miR-181a overexpression improved cardiac function and deactivated Aldo-MR pathway proving a cardio-protective role of miR-181a. Global RNA sequencing of cells under Aldo treatment with/without miR-181a overexpression identified potential miR-181a targets functionally contributing to Aldo-MR pathway. Adamts1, a direct target of miR-181a, was found to be downregulated with miR-181a overexpression and upregulated with inhibition. Similar to miR-181a overexpression, siRNA-mediated inhibition of Adamts1 inhibited Aldo-MR pathway.
CONCLUSION: We here show that miR-181a is a novel regulator of the Aldo-MR pathway regulating the levels of Ngal via direct targeting of Adamts1. This new insight establishes miR-181a as a factor of immense value participating in downstream networks of Aldo-MR pathway. Our in vivo studies further confirmed miR-181a as cardio-protective under MI stress. Thus, miR-181a's involvement in Aldo-MR-mediated cardiac remodelling confers it with tremendous potential to be developed further as a new therapeutic target.
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