Nagy Regina N, Makkos András, Baranyai Tamás, Giricz Zoltán, Szabó Márta, Kravcsenko-Kiss Bernadett, Bereczki Zoltán, Ágg Bence, Puskás László G, Faragó Nóra, Schulz Rainer, Gyöngyösi Mariann, Lukovic Dominika, Varga Zoltán V, Görbe Anikó, Ferdinandy Péter
Cardiometabolic and HUN-REN-SU System Pharmacology Research Group, Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
Pharmahungary Group, Szeged, Hungary.
Br J Pharmacol. 2025 Jan;182(2):396-416. doi: 10.1111/bph.17313. Epub 2024 Sep 18.
Cardioprotective miRNAs (protectomiRs) are promising therapeutic tools. Here, we aimed to identify protectomiRs in a translational porcine model of acute myocardial infarction (AMI) and to validate their cardiocytoprotective effect.
ProtectomiR candidates were selected after systematic analysis of miRNA expression changes in cardiac tissue samples from a closed-chest AMI model in pigs subjected to sham operation, AMI and ischaemic preconditioning, postconditioning or remote preconditioning, respectively. Cross-species orthologue protectomiR candidates were validated in simulated ischaemia-reperfusion injury (sI/R) model of isolated rat ocardiomyocytes and in human AC16 cells as well. For miR-450a, we performed target prediction and analysed the potential mechanisms of action by GO enrichment and KEGG pathway analysis.
Out of the 220 detected miRNAs, four were up-regulated and 10 were down-regulated due to all three conditionings versus AMI. MiR-450a and miR-451 mimics at 25 nM were protective in rat cardiomyocytes, and miR-450a showed protection in human cardiomyocytes as well. MiR-450a has 3987 predicted mRNA targets in pigs, 4279 in rats and 8328 in humans. Of these, 607 genes are expressed in all three species. A total of 421 common enriched GO terms were identified in all three species, whereas KEGG pathway analysis revealed 13 common pathways.
This is the first demonstration that miR-450a is associated with cardioprotection by ischaemic conditioning in a clinically relevant porcine model and shows cardiocytoprotective effect in human cardiomyocytes, making it a promising drug candidate. The mechanism of action of miR-450a involves multiple cardioprotective pathways.
This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.
具有心脏保护作用的微小RNA（心脏保护微小RNA）是很有前景的治疗工具。在此，我们旨在鉴定急性心肌梗死（AMI）的转化猪模型中的心脏保护微小RNA，并验证其对心肌细胞的保护作用。
在对分别接受假手术、急性心肌梗死以及缺血预处理、后处理或远程预处理的猪的闭胸急性心肌梗死模型心脏组织样本中的微小RNA表达变化进行系统分析后，筛选出心脏保护微小RNA候选物。跨物种直系同源心脏保护微小RNA候选物在分离的大鼠心肌细胞模拟缺血再灌注损伤（sI/R）模型以及人AC16细胞中也得到了验证。对于miR-450a，我们进行了靶标预测，并通过基因本体论（GO）富集分析和京都基因与基因组百科全书（KEGG）通路分析来分析其潜在作用机制。
在检测到的220种微小RNA中，与急性心肌梗死相比，所有三种预处理条件均导致4种微小RNA上调，10种微小RNA下调。25 nM的miR-450a和miR-451模拟物对大鼠心肌细胞具有保护作用，miR-450a对人心肌细胞也具有保护作用。miR-450a在猪中有3987个预测的mRNA靶标，在大鼠中有4279个，在人中有8328个。其中，607个基因在所有三个物种中均有表达。在所有三个物种中总共鉴定出421个共同富集的GO术语，而KEGG通路分析揭示了13条共同通路。
这是首次证明miR-450a在临床相关的猪模型中与缺血预处理的心脏保护作用相关，并在人心肌细胞中显示出心肌细胞保护作用，使其成为一个有前景的药物候选物。miR-450a的作用机制涉及多种心脏保护通路。
本文是主题为“非编码RNA治疗学”的特刊的一部分。若要查看本部分的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc。
