斯坦福A型主动脉夹层中与病理相关及具有诊断潜力的环状RNA的鉴定
Identification of pathological-related and diagnostic potential circular RNAs in Stanford type A aortic dissection.
作者信息
Liang Qiao, Zhou Zeyi, Li Hui, Tao Qing, Wang Yali, Lin Anqi, Xu Jing, Zhang Bin, Wu Yongzheng, Min Haiyan, Wang Lei, Song Shiyu, Wang Dongjin, Gao Qian
机构信息
Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China.
Department of Thoracic and Cardiovascular Surgery, Institute of Cardiothoracic Vascular Disease, Nanjing University, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
出版信息
Front Cardiovasc Med. 2023 Jan 13;9:1074835. doi: 10.3389/fcvm.2022.1074835. eCollection 2022.
INTRODUCTION
Stanford type A aortic dissection (TAAD) is one of the lethal macrovascular diseases caused by the invasion of blood into the media layer of ascending aortic wall. Inflammation, smooth muscle dysfunction, and extracellular matrix (ECM) degradation were regarded as the major pathology in affected tissue. However, the expression pattern and its regulation especially through circular RNAs (circRNAs) as an overall characteristic of TAAD molecular pathology remain unclear.
METHODS
We employed CIRCexplorer2 to identify circRNAs based on the RNA sequencing (RNA-seq) data of human ascending aortic tissues to systematically assess the role of circRNA in the massive alterations of gene expression in TAAD aortas. The key circRNAs were determined by LASSO model and functionally annotated by competing endogenous RNAs (ceRNA) network and co-analysis with mRNA profile. The expression level and diagnostic capability of the 4 key circRNAs in peripheral serum were confirmed by real-time polymerase chain reaction (RT-PCR).
RESULTS
The 4 key circRNAs, namely circPTGR1 (chr9:114341075-114348445[-]), circNOX4 (chr11:89069012-89106660[-]), circAMN1 (chr12:31854796-31862359[-]) and circUSP3 (chr15:63845913-63855207[+]), demonstrated a high power to discriminate between TAAD and control tissues, suggesting that these molecules stand for a major difference between the tissues at gene regulation level. Functionally, the ceRNA network of circRNA-miRNA-mRNA predicted by the online databases, combining gene set enrichment analysis (GSEA) and cell component prediction, revealed that the identified circRNAs covered all the aspects of primary TAAD pathology, centralized with increasing inflammatory factors and cells, and ECM destruction and loss of vascular inherent cells along with the circRNAs. Importantly, we validated the high concentration and diagnostic capability of the 4 key circRNAs in the peripheral serum in TAAD patients.
DISCUSSION
This study reinforces the vital status of circRNAs in TAAD and the possibility of serving as promising diagnostic biomarkers.
引言
斯坦福A型主动脉夹层（TAAD）是一种因血液侵入升主动脉壁中层而引发的致命性大血管疾病。炎症、平滑肌功能障碍和细胞外基质（ECM）降解被视为病变组织的主要病理特征。然而，作为TAAD分子病理学的整体特征，环状RNA（circRNA）的表达模式及其调控，尤其是通过circRNA的调控，仍不清楚。
方法
我们利用CIRCexplorer2基于人类升主动脉组织的RNA测序（RNA-seq）数据来鉴定circRNA，以系统评估circRNA在TAAD主动脉基因表达大量改变中的作用。通过LASSO模型确定关键circRNA，并通过竞争性内源RNA（ceRNA）网络以及与mRNA谱的联合分析进行功能注释。通过实时聚合酶链反应（RT-PCR）确认4种关键circRNA在外周血清中的表达水平和诊断能力。
结果
4种关键circRNA，即circPTGR1（chr9:114341075 - 114348445[-]）、circNOX4（chr11:89069012 - 89106660[-]）、circAMN1（chr12:31854796 - 31862359[-]）和circUSP3（chr15:63845913 - 63855207[+]），在区分TAAD组织和对照组织方面具有很高的效能，这表明这些分子在基因调控水平上代表了组织之间的主要差异。在功能上，通过在线数据库预测的circRNA - miRNA - mRNA的ceRNA网络，结合基因集富集分析（GSEA）和细胞成分预测，显示所鉴定的circRNA涵盖了原发性TAAD病理学的所有方面，随着circRNA的增加，炎症因子和细胞、ECM破坏以及血管固有细胞的丧失都集中出现。重要的是，我们验证了TAAD患者外周血清中4种关键circRNA的高浓度及诊断能力。
讨论
本研究强化了circRNA在TAAD中的重要地位以及其作为有前景的诊断生物标志物的可能性。
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