Expression Profiles of Circular RNA in Aortic Vascular Tissues of Spontaneously Hypertensive Rats

Abstract

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.

Targeting the microRNA-34a as a Novel Therapeutic Strategy for Cardiovascular Diseases

“…Primary hypertension is a common chronic disease that usually causes other health complications, such as coronary artery disease, stroke, renal failure and heart failure, and poses a great threat to human health (89,90). Currently, the relationship between miR-34a and hypertension is relatively limited (91).…”

Profile analysis and functional modeling identify circular RNAs in nonalcoholic fatty liver disease as regulators of hepatic lipid metabolism

“…Compared to the low-level threshold with score >140 and energy < −10 in miRanda prediction, our study employed a threshold with score >180 and energy < −30 for the highest accuracy and confidence in the prediction of circRNA-miRNA interactions ( Li et al, 2018b ; Li et al, 2019b ; Li et al, 2020 ; Cao et al, 2021 ). Similarly, the miRNA-mRNA interactions identified by ≥ 6 databases and miRDB score ≥80 are supposed to be different, to some extent, from those obtained by one to three databases ( Li et al, 2019b ; Cao et al, 2021 ; Liu et al, 2021 ). Although the circRNA-miRNA and miRNA-mRNA interactions were of high confidence, in vivo and/or in vitro investigation will be valuable.…”

Circular RNAs as a Diagnostic and Therapeutic Target in Cardiovascular Diseases

“…Liu et al, [24] found 485 differentially expressed circRNAs in aortic vascular tissue of spontaneously hypertensive rats (SHR) when compared to Wistar Kyoto (WKT) rats. Three circRNA-miRNA-mRNA axes were predicted and later confirmed in SHR aortas, regulating the NOTCH1, FOXO3, and STAT3 genes, all of which are involved in vascular diseases.…”