Circular RNA hsa_circ_0014243 may serve as a diagnostic biomarker for essential hypertension

Zheng,Shuying; Gu,Tianlun; Bao,Xingjie; Sun,Jihan; Zhao,Jinshun; Zhang,Tao; Zhang,Lina

doi:10.3892/etm.2018.7107

Circular RNA hsa_circ_0014243 may serve as a diagnostic biomarker for essential hypertension

Authors:
- Shuying Zheng
- Tianlun Gu
- Xingjie Bao
- Jihan Sun
- Jinshun Zhao
- Tao Zhang
- Lina Zhang
View Affiliations

Affiliations: Department of Preventive Medicine, Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, P.R. China, Department of Clinical Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P.R. China, Department of Chronic Disease Control and Prevention, Ningbo Municipal Center for Disease Control and Prevention, Ningbo, Zhejiang 315000, P.R. China
Published online on: December 17, 2018 https://doi.org/10.3892/etm.2018.7107
Pages: 1728-1736
Copyright: © Zheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Circular RNAs (circRNAs) have a great potential as clinical biomarkers; however, specific circRNAs with a diagnostic value for essential hypertension (EH) largely remain to be identified. In the present study, the potential application of Homo sapiens (hsa)_circ_0014243, which was identified to be significantly upregulated in whole blood samples of EH patients in a previous microarray profiling study by our group, in the diagnosis of EH was evaluated. Reverse transcription‑quantitative polymerase chain reaction analysis was performed to determine the expression levels of hsa_circ_0014243 and hsa‑microRNA (miR)‑10a‑5p in a total of 178 blood samples collected from 89 healthy controls and 89 patients diagnosed with EH. Divergent primers were designed for circRNAs, while conventional primers were used for miRs. Independent‑samples t‑tests and bivariate correlation analyses were performed to analyze the association between clinical factors influencing EH and hsa_circ_0014243 expression levels. A receiver operating characteristics (ROC) curve was generated to estimate the diagnostic value of hsa_circ_0014243 for EH. Finally, the expression levels of circRNAs and miRNAs were combined to propose a possible prediction model for EH. The results indicated that hsa_circ_0014243 was upregulated in whole blood samples of EH patients compared with that in the controls (P<0.001). Furthermore, the relative expression levels of hsa_circ_0014243 (Δ quantification cycle) were identified to be significantly correlated with age (r=‑0.259, P<0.001), high‑density lipoprotein levels (r=0.196, P=0.009) and glucose levels (r=‑0.204, P=0.006). The area under the ROC curve (AUC) of the model using hsa_circ_0014243 as a predictor was 0.732. Of note, the AUC increased to 0.781 when hsa_circ_0014243 levels were combined with hsa‑miR‑10a‑5p levels as predictors. The present results suggest that hsa_circ_0014243 has a crucial role in the genesis and development of EH, and presents a certain diagnostic capability for EH.

View Figures

View References

1	Staessen JA, Wang J, Bianchi G and Birkenhäger WH: Essential hypertension. Lancet. 361:1629–1641. 2003. View Article : Google Scholar : PubMed/NCBI
2	Mao S, Gu T, Zhong F, Fan R, Zhu F, Ren P, Yin F and Zhang L: Hypomethylation of the Toll-like receptor-2 gene increases the risk of essential hypertension. Mol Med Rep. 16:964–970. 2017. View Article : Google Scholar : PubMed/NCBI
3	Savoia C, Sada L, Zezza L, Pucci L, Lauri FM, Befani A, Alonzo A and Volpe M: Vascular inflammation and endothelial dysfunction in experimental hypertension. Int J Hypertens. 2011:2812402011. View Article : Google Scholar : PubMed/NCBI
4	Mao SQ, Sun JH, Gu TL, Zhu FB, Yin FY and Zhang LN: Hypomethylation of interleukin-6 (IL-6) gene increases the risk of essential hypertension: A matched case-control study. J Hum Hypertens. 31:530–536. 2017. View Article : Google Scholar : PubMed/NCBI
5	Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, et al: Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 495:333–338. 2013. View Article : Google Scholar : PubMed/NCBI
6	Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK and Kjems J: Natural RNA circles function as efficient microRNA sponges. Nature. 495:384–388. 2013. View Article : Google Scholar : PubMed/NCBI
7	Huang XY, Huang ZL, Xu YH, Zheng Q, Chen Z, Song W, Zhou J, Tang ZY and Huang XY: Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-100338/miR-141-3p pathway in hepatitis B-related hepatocellular carcinoma. Sci Rep. 7:54282017. View Article : Google Scholar : PubMed/NCBI
8	Chen Y, Li C, Tan C and Liu X: Circular RNAs: A new frontier in the study of human diseases. J Med Genet. 53:359–365. 2016. View Article : Google Scholar : PubMed/NCBI
9	Jin X, Feng CY, Xiang Z, Chen YP and Li YM: CircRNA expression pattern and circRNA-miRNA-mRNA network in the pathogenesis of nonalcoholic steatohepatitis. Oncotarget. 7:66455–66467. 2016. View Article : Google Scholar : PubMed/NCBI
10	Qu S, Yang X, Li X, Wang J, Gao Y, Shang R, Sun W, Dou K and Li H: Circular RNA: A new star of noncoding RNAs. Cancer Lett. 365:141–148. 2015. View Article : Google Scholar : PubMed/NCBI
11	Memczak S, Papavasileiou P, Peters O and Rajewsky N: Identification and characterization of circular RNAs as a new class of putative biomarkers in human blood. PLoS One. 10:e01412142015. View Article : Google Scholar : PubMed/NCBI
12	Michell DL and Vickers KC: HDL and microRNA therapeutics in cardiovascular disease. Pharmacol Ther. 168:43–52. 2016. View Article : Google Scholar : PubMed/NCBI
13	Shi L, Liao J, Liu B, Zeng F and Zhang L: Mechanisms and therapeutic potential of microRNAs in hypertension. Drug Discov Today. 20:1188–1204. 2015. View Article : Google Scholar : PubMed/NCBI
14	Zheng L, Xu CC, Chen WD, Shen WL, Ruan CC, Zhu LM, Zhu DL and Gao PJ: MicroRNA-155 regulates angiotensin II type 1 receptor expression and phenotypic differentiation in vascular adventitial fibroblasts. Biochem Biophys Res Commun. 400:483–488. 2010. View Article : Google Scholar : PubMed/NCBI
15	Njock MS, Cheng HS, Dang LT, Nazari-Jahantigh M, Lau AC, Boudreau E, Roufaiel M, Cybulsky MI, Schober A and Fish JE: Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs. Blood. 125:3202–3212. 2015. View Article : Google Scholar : PubMed/NCBI
16	Bao X, Zheng S, Mao S, Gu T, Liu S, Sun J and Zhang L: A potential risk factor of essential hypertension in case-control study: Circular RNA hsa_circ_0037911. Biochem Biophys Res Commun. 498:789–794. 2018. View Article : Google Scholar : PubMed/NCBI
17	Burnier M, Oparil S, Narkiewicz K and Kjeldsen SE: New 2017 American Heart Association and American College of Cardiology guideline for hypertension in the adults: Major paradigm shifts, but will they help to fight against the hypertension disease burden? Blood Press. 27:62–65. 2018. View Article : Google Scholar : PubMed/NCBI
18	Shao Y, Chen L, Lu R, Zhang X, Xiao B, Ye G and Guo J: Decreased expression of hsa_circ_0001895 in human gastric cancer and its clinical significances. Tumour Biol. 39:10104283176991252017. View Article : Google Scholar : PubMed/NCBI
19	Zhao Z, Li X, Gao C, Jian D, Hao P, Rao L and Li M: Peripheral blood circular RNA hsa_circ_0124644 can be used as a diagnostic biomarker of coronary artery disease. Sci Rep. 7:399182017. View Article : Google Scholar : PubMed/NCBI
20	Hijmans JG, Diehl KJ, Bammert TD, Kavlich PJ, Lincenberg GM, Greiner JJ, Stauffer BL and DeSouza CA: Association between hypertension and circulating vascular-related microRNAs. J Hum Hypertens. 32:440–447. 2018. View Article : Google Scholar : PubMed/NCBI
21	Shao Y, Ye M, Jiang X, Sun W, Ding X, Liu Z, Ye G, Zhang X, Xiao B and Guo J: Gastric juice long noncoding RNA used as a tumor marker for screening gastric cancer. Cancer. 120:3320–3328. 2014. View Article : Google Scholar : PubMed/NCBI
22	Schellingerhout JM, Heymans MW, de Vet HC, Koes BW and Verhagen AP: Categorizing continuous variables resulted in different predictors in a prognostic model for nonspecific neck pain. J Clin Epidemiol. 62:868–874. 2009. View Article : Google Scholar : PubMed/NCBI
23	Fang Y, Shi C, Manduchi E, Civelek M and Davies PF: MicroRNA-10a regulation of proinflammatory phenotype in athero-susceptible endothelium in vivo and in vitro. Proc Natl Acad Sci USA. 107:13450–13455. 2010. View Article : Google Scholar : PubMed/NCBI
24	Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, Marzluff WF and Sharpless NE: Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 19:141–157. 2013. View Article : Google Scholar : PubMed/NCBI
25	Yang F, Liu DY, Guo JT, Ge N, Zhu P, Liu X, Wang S, Wang GX and Sun SY: Circular RNA circ-LDLRAD3 as a biomarker in diagnosis of pancreatic cancer. World J Gastroenterol. 23:8345–8354. 2017. View Article : Google Scholar : PubMed/NCBI
26	Xie Y, Shao Y, Sun W, Ye G, Zhang X, Xiao B and Guo J: Downregulated expression of hsa_circ_0074362 in gastric cancer and its potential diagnostic values. Biomark Med. 12:11–20. 2018. View Article : Google Scholar : PubMed/NCBI
27	Jiang XM, Li ZL, Li JL, Xu Y, Leng KM, Cui YF and Sun DJ: A novel prognostic biomarker for cholangiocarcinoma: CircRNA Cdr1as. Eur Rev Med Pharmacol Sci. 22:365–371. 2018.PubMed/NCBI
28	Wang K, Long B, Liu F, Wang JX, Liu CY, Zhao B, Zhou LY, Sun T, Wang M, Yu T, et al: A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223. Eur Heart J. 37:2602–2611. 2016. View Article : Google Scholar : PubMed/NCBI
29	Wang J, Zhang L, Wang F, Liu L and Wang H: China National Survey of Chronic Kidney Disease Working Group: Prevalence, awareness, treatment, and control of hypertension in China: Results from a national survey. Am J Hypertens. 27:1355–1361. 2014. View Article : Google Scholar : PubMed/NCBI
30	Willinger CM, Rong J, Tanriverdi K, Courchesne PL, Huan T, Wasserman GA, Lin H, Dupuis J, Joehanes R, Jones MR, et al: MicroRNA signature of cigarette smoking and evidence for a putative causal role of MicroRNAs in smoking-related inflammation and target organ damage. Circ Cardiovasc Genet. 10:e0016782017. View Article : Google Scholar : PubMed/NCBI
31	Lin CY, Wan LM, Chen YQ, Ou HT, Zhao L, Liang YT, Ma R, Lu WJ and Wang J: Cigarette smoke exposure induced pulmonary artery pressure increase through inhibiting Kv1.5 and Kv2.1 mRNA expression in rat pulmonary artery smooth muscles. Zhonghua Jie He He Hu Xi Za Zhi. 35:695–699. 2012.(In Chinese). PubMed/NCBI
32	Arnold AC, Gallagher PE and Diz DI: Brain renin-angiotensin system in the nexus of hypertension and aging. Hypertens Res. 36:5–13. 2013. View Article : Google Scholar : PubMed/NCBI
33	Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, et al: The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report. JAMA. 289:2560–2572. 2003. View Article : Google Scholar : PubMed/NCBI
34	Westholm JO, Miura P, Olson S, Shenker S, Joseph B, Sanfilippo P, Celniker SE, Graveley BR and Lai EC: Genome-wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation. Cell Rep. 9:1966–1980. 2014. View Article : Google Scholar : PubMed/NCBI
35	Cortés-López M, Gruner MR, Cooper DA, Gruner HN, Voda AI, van der Linden AM and Miura P: Global accumulation of circRNAs during aging in Caenorhabditis elegans. BMC Genomics. 19:82018. View Article : Google Scholar : PubMed/NCBI
36	Cheng J, Huang J, Yuan S, Zhou S, Yan W, Shen W, Chen Y, Xia X, Luo A, Zhu D and Wang S: Circular RNA expression profiling of human granulosa cells during maternal aging reveals novel transcripts associated with assisted reproductive technology outcomes. PLoS One. 12:e01778882017. View Article : Google Scholar : PubMed/NCBI
37	Guo JN, Li J, Zhu CL, Feng WT, Shao JX, Wan L, Huang MD and He JD: Comprehensive profile of differentially expressed circular RNAs reveals that hsa_circ_0000069 is upregulated and promotes cell proliferation, migration, and invasion in colorectal cancer. Onco Targets Ther. 9:7451–7458. 2016. View Article : Google Scholar : PubMed/NCBI
38	Gruner H, Cortés-López M, Cooper DA, Bauer M and Miura P: CircRNA accumulation in the aging mouse brain. Sci Rep. 6:389072016. View Article : Google Scholar : PubMed/NCBI