Expression Profiles of Circular RNA in Aortic Vascular Tissues of Spontaneously Hypertensive Rats.
Expression Profiles of Circular RNA in Aortic Vascular Tissues of Spontaneously Hypertensive Rats.
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自发性高血压大鼠主动脉血管组织中环状RNA的表达谱
DOI：
10.3389/fcvm.2021.814402
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发表时间：
2021
影响因子：
3.6
通讯作者：
Zhong J
中科院分区：
文献类型：
--
作者：
Liu Y;Dong Y;Dong Z;Song J;Zhang Z;Liang L;Liu X;Sun L;Li X;Zhang M;Chen Y;Miao R;Zhong J
背景：环状RNA（circRNA）作为一种内源性非编码RNA，与缺血性心脏病和血管疾病有关。基于其闭环结构的高稳定性，circRNA起到海绵的作用，结合特定的miRNA，在心脏和脉管系统中发挥抑制作用，从而通过竞争性内源RNA（ceRNA）机制调节其靶基因和蛋白质的表达。然而，circRNA 在高血压和相关心血管疾病中的确切作用和潜在机制仍然很大程度上未知。方法和结果：采用高通量RNA测序（RNA-seq）分析自发性高血压大鼠（SHR）主动脉血管组织中差异表达（DE）的circRNA。与 Wistar-Kyoto (WKY) 大鼠相比，通过尾套方法，清醒条件下 SHR 的收缩压、舒张压和平均血压水平显着升高。与WKY大鼠相比，SHR主动脉血管组织中共发现485个DE circRNA，其中279个上调circRNA和206个下调circRNA。此外，分别通过miRanda和Targetscan软件预测了circRNA目标microRNA（miRNA）和miRNA的目标信使RNA（mRNA）。此外，实时RT-PCR分析证实，与WKY大鼠相比，SHR主动脉中观察到rno_circRNA_0009197下调，rno_circRNA_0005818、rno_circRNA_0005304、rno_circRNA_0005506和rno_circRNA_0009301上调。然后，通过整合 5 个已验证的 circRNA、31 个预测的 miRNA 和 266 个目标 mRNA，构建了潜在的 ceRNA 调控机制。更重要的是，根据PPI网络识别了三个枢纽基因（NOTCH1、FOXO3和STAT3），并在高血压大鼠主动脉中发现了三个有前途的circRNA-miRNA-mRNA调控轴，包括rno_circRNA_0005818/miR-615/NOTCH1、rno_circRNA_0009197/miR-509-5p/FOXO3和分别为rno_circRNA_0005818/miR-10b-5p/STAT3。结论：我们的研究结果首次证明，circRNA在高血压大鼠主动脉血管组织中异常表达，并可能通过circRNA-miRNA-mRNA ceRNA网络机制，作为海绵连接参与高血压及相关缺血性心脏病发病机制的相关miRNA。
Background: Circular RNAs (circRNAs), as a kind of endogenous non-coding RNA, have been implicated in ischemic heart diseases and vascular diseases. Based on theirs high stability with a closed loop structure, circRNAs function as a sponge and bind specific miRNAs to exert inhibitory effects in heart and vasculature, thereby regulating their target gene and protein expression, via competitive endogenous RNA (ceRNA) mechanism. However, the exact roles and underlying mechanisms of circRNAs in hypertension and related cardiovascular diseases remain largely unknown. Methods and Results: High-throughput RNA sequencing (RNA-seq) was used to analyze the differentially expressed (DE) circRNAs in aortic vascular tissues of spontaneously hypertensive rats (SHR). Compared with the Wistar-Kyoto (WKY) rats, there were marked increases in the levels of systolic blood pressure, diastolic blood pressure and mean blood pressure in SHR under awake conditions via the tail-cuff methodology. Totally, compared with WKY rats, 485 DE circRNAs were found in aortic vascular tissues of SHR with 279 up-regulated circRNAs and 206 down-regulated circRNAs. Furthermore, circRNA-target microRNAs (miRNAs) and the target messenger RNAs (mRNAs) of miRNAs were predicted by the miRanda and Targetscan softwares, respectively. Additionally, real-time RT-PCR analysis verified that downregulation of rno_circRNA_0009197, and upregulation of rno_circRNA_0005818, rno_circRNA_0005304, rno_circRNA_0005506, and rno_circRNA_0009301 were observed in aorta of SHR when compared with that of WKY rats. Then, the potential ceRNA regulatory mechanism was constructed via integrating 5 validated circRNAs, 31 predicted miRNAs, and 266 target mRNAs. More importantly, three hub genes (NOTCH1, FOXO3, and STAT3) were recognized according to PPI network and three promising circRNA-miRNA-mRNA regulatory axes were found in hypertensive rat aorta, including rno_circRNA_0005818/miR-615/NOTCH1, rno_circRNA_0009197/ miR-509-5p/FOXO3, and rno_circRNA_0005818/miR-10b-5p/STAT3, respectively. Conclusions: Our results demonstrated for the first time that circRNAs are expressed aberrantly in aortic vascular tissues of hypertensive rats and may serve as a sponge linking with relevant miRNAs participating in pathogenesis of hypertension and related ischemic heart diseases via the circRNA-miRNA-mRNA ceRNAnetwork mechanism.
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