Hypertension (HT), or high blood pressure (BP), is a chronic disease that is common among populations worldwide. The occurrence of HT is one of the leading causes of cardiovascular morbidity and mortality in adults. Although multiple studies have stressed the multifactorial and multigenic nature of HT, uncertainties about its etiology persist, and current diagnostic biomarkers can explain only a small part of the phenotypic variance of BP. Hence, the search for novel biomarkers that enable early disease prevention and guided therapy is warranted. Regulatory circRNAs have emerged as the newest player in HT-related gene networks and hold promise for improving the accuracy of diagnosis. These RNAs are genome products that are formed through back-splicing of specific regions of pre-mRNAs. Evidence suggests that these RNA species are involved in various metabolic diseases. Recent studies have revealed that aberrant expression of circRNAs is relevant to the occurrence and development of HT. Accordingly, circRNAs are proposed as a new generation of predictive biomarkers and potential therapeutic targets for different forms of HT, including pulmonary hypertension and preeclampsia. This paper presents an overview of the findings from current research focusing on the emerging role of circRNAs in the pathogenesis of hypertension. Furthermore, some of the challenges encountered by circRNA studies are highlighted, and perspectives are provided on the future of research in this area.
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Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365:217–23.
Poulter NR, Prabhakaran D, Caulfield M. Hypertension. Lancet 2015;386:801–12.
Carretero OA, Oparil S. Essential hypertension. Part I: definition and etiology. Circulation 2000;101:329–35. 2000
Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. Ann Intern Med. 2003;139:761–76.
Hall WD. Risk reduction associated with lowering systolic blood pressure: review of clinical trial data. Am Heart J. 1999;138:225–30.
NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19·1 million participants. Lancet 2017;389:37–55.
Marteau JB, Zaiou M, Siest G, Visvikis-Siest S. Genetic determinants of blood pressure regulation. J Hypertens. 2005;23:2127–43.
Simon PH, Sylvestre MP, Tremblay J, Hamet P. Key considerations and methods in the study of gene-environment interactions. Am J Hypertens. 2016;29:891–9.
Wise IA, Charchar FJ. Epigenetic modifications in essential hypertension. Int J Mol Sci. 2016;17:451. https://doi.org/10.3390/ijms17040451
Rossier BC, Bochud M, Devuyst O. The hypertension pandemic: an evolutionary perspective. Physiol. 2017;32:112–25.
Wolf-Maier K, Cooper RS, Kramer H, Banegas JR, Giampaoli S, Joffres MR, et al. Hypertension treatment and control in five European countries, Canada, and the United States. Hypertension 2004;43:10–7.
Kupper N, Willemsen G, Riese H, Posthuma D, Boomsma DI, de Geus EJ. Heritability of daytime ambulatory blood pressure in an extended twin design. Hypertension 2005;45:80–85.
Tanira MO, Al Balushi KA. Genetic variations related to hypertension: a review. J Hum Hypertens. 2005;19:7–19.
Tragante V, Barnes MR, Ganesh SK, Lanktree MB, Guo W, Franceschini N, et al. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci. Am J Hum Genet. 2014;94:349–60.
Bayoglu B, Yuksel H, Cakmak HA, Dirican A, Cengiz M. Polymorphisms in the long non-coding RNA CDKN2B-AS1 may contribute to higher systolic blood pressure levels in hypertensive patients. Clin Biochem. 2016;49:821–7.
Hoffmann TJ, Ehret GB, Nandakumar P, Ranatunga D, Schaefer C, Kwok PY, et al. Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation. Nat Genet. 2017;49:54–64.
Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009;41:666–76.
Ehret GB, Ferreira T, Chasman DI, Jackson AU, Schmidt EM, Johnson T, et al. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet. 2016;48:1171–84.
Bátkai S, Thum T. MicroRNAs in hypertension: mechanisms and therapeutic targets. Curr Hypertens Rep. 2012;14:79–87.
Deng L, Bradshaw AC, Baker AH. Role of noncoding RNA in vascular remodelling. Curr Opin Lipido. 2016;27:439–48.
Lorenzen JM, Thum T. Long noncoding RNAs in kidney and cardiovascular diseases. Nat Rev Nephrol. 2016;12:360–73.
Starke S, Jost I, Rossbach O, Schneider T, Schreiner S, Hung LH, et al. Exon circularization requires canonical splice signals. Cell Rep. 2015;10:103–11.
Chen LL. The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol. 2016;17:205–11.
Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 2013;19:141–57.
Chen LL, Yang L. Regulation of circRNA biogenesis. RNA Biol. 2015;12:381–8.
Enuka Y, Lauriola M, Feldman ME, Sas-Chen A, Ulitsky I, Yarden Y. Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor. Nucleic Acids Res. 2016;44:1370–83.
Dragomir M, Calin GA. Circular RNAs in Cancer - Lessons Learned From microRNAs. Front Oncol. 2018;8:179. https://doi.org/10.3389/fonc.2018.00307
Li X, Yang L, Chen LL. The biogenesis, functions, and challenges of circular RNAs. Mol Cell 2018;71:428–42.
Xu Y. An overview of the main circRNA databases. Non-coding RNA Invest. 2017;1:22. https://doi.org/10.21037/ncri.2017.11.05
Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS ONE. 2012;7:e30733. https://doi.org/10.1371/journal.pone.0030733
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 2013;495:333–8.
Guo JU, Agarwal V, Guo H, Bartel DP. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 2014;15:409. https://doi.org/10.1186/s13059-014-0409-z
Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, et al. The RNA binding protein quaking regulates formation of circRNAs. Cell 2015;160:1125–34.
Salzman J, Chen RE, Olsen MN, Wang PL, Brown PO. Cell-type specific features of circular RNA expression. PLoS Genet. 2013;9:e1003777. https://doi.org/10.1371/journal.pone.0030733
You X, Vlatkovic I, Babic A, Will T, Epstein I, Tushev G, et al. Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci. 2015;18:603–10.
Rybak-Wolf A, Stottmeister C, Glažar P, Jens M, Pino N, Giusti S, et al. Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell 2015;58:870–85.
Hanan M, Soreq H, Kadener S. CircRNAs in the brain. RNA Biol. 2017;14:1028–34.
Piwecka M, Glažar P, Hernandez-Miranda LR, Memczak S, Wolf SA, Rybak-Wolf A, et al. Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science. 2017;357:eaam8526. https://doi.org/10.1126/science.aam8526
Nigro JM, Cho KR, Fearon ER, Kern SE, Ruppert JM, Oliner JD, et al. Scrambled exons. Cell 1991;64:607–13.
Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, et al. circRNA biogenesis competes with pre-mRNA splicing. Mol Cell 2014;56:55–66.
Kellis M, Wold B, Snyder MP, Bernstein BE, Kundaje A, Marinov GK. Defining functional DNA elements in the human genome. Proc Natl Acad Sci USA. 2014;111:6131–8.
Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2018;22:256–64.
Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature 2013;495:384–8.
Hentze MW, Preiss T. Circular RNAs: splicing’s enigma variations. EMBO J. 2013;2013:923–5.
Du WW, Zhang C, Yang W, Yong T, Awan FM, Yang BB. Identifying and Characterizing circRNA-Protein Interaction. Theranostics. 2017;7:4183–91.
Holdt LM, Kohlmaier A, Teupser D. Molecular roles and function of circular RNAs in eukaryotic cells. Cell Mol Life Sci. 2018;75:1071–98.
Zhong Y, Du Y, Yang X, Mo Y, Fan C, Xiong F, et al. Circular RNAs function as ceRNAs to regulate and control human cancer progression. Mol Cancer. 2018;17:79. https://doi.org/10.1186/s12943-018-0827-8
Li M, Ding W, Sun T, Tariq MA, Xu T, Li P, et al. Biogenesis of circular RNAs and their roles in cardiovascular development and pathology. FEBS J. 2018;285:220–32.
Floris G, Zhang L, Follesa P, Sun T. Regulatory role of circular RNAs and neurological disorders. Mol Neurobiol. 2017;54:5156–65.
Boeckel JN, Jaé N, Heumüller AW, Chen W, Boon RA, Stellos K, et al. Identification and Characterization of Hypoxia-regulated Endothelial Circular RNA. Circ Res. 2015;2015:884–90.
Zaiou M. Circular RNAs as potential biomarkers and therapeutic targets for metabolic diseases. In: Guest PC, editor. Reviews on biomarker studies of metabolic and metabolism-related disorders. Adv Exp Med Biol. 2019;1134. https://doi.org/10.1007/978-3-030-12668-1_10 (in press)
Bayoumi AS, Aonuma T, Teoh JP, Tang YL, Kim IM. Circular noncoding RNAs as potential therapies and circulating biomarkers for cardiovascular diseases. Acta Pharm Sin. 2018;39:1100–9.
Guay C, Regazzi R. Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat Rev Endocrinol. 2013;9:513–21.
Tang Y, Zhou T, Yu X, Xue Z, Shen N. The role of long non-coding RNAs in rheumatic diseases. Nat Rev Rheuma. 2017;13:657–69.
Gangwar RS, Rajagopalan S, Natarajan R, Deiuliis JA. Noncoding RNAs in cardiovascular disease: pathological relevance and emerging role as biomarkers and therapeutics. Am J Hypertens. 2018;31:150–65.
Zaiou M, El Amri H, Bakillah A. The clinical potential of adipogenesis and obesity-related microRNAs. Nutr Metab Cardiovasc Dis. 2018;28:91–111.
Zaiou M, Bakillah A. Epigenetic regulation of ATP-binding cassette protein A1 (ABCA1) gene expression: a new era to alleviate atherosclerotic cardiovascular disease. Diseases. 2018;6:E34. https://doi.org/10.3390/diseases6020034
Li X, Wei Y, Wang Z. microRNA-21 and hypertension. Hypertens Res. 2018;41:649–61.
Leimena C, Qiu H, Non-Coding RNA. in the pathogenesis, progression and treatment of hypertension. Int J Mol Sci. 2018;19:E927. https://doi.org/10.3390/ijms19040927
Baker MA, Wang F, Liu Y, Kriegel AJ, Geurts AM, Usa K, et al. MiR-192-5p in the kidney protects against the development of hypertension. Hypertension 2019;73:399–406. https://doi.org/10.1161/HYPERTENSIONAHA.118.11875
Krishnan R, Mani P, Sivakumar P, Gopinath V, Sekar D. Expression and methylation of circulating microRNA-510 in essential hypertension. Hypertens Res. 2017;40:361–3.
Xu YP, He Q, Shen Z, Shu XL, Wang CH, Zhu JJ, et al. MiR-126a-5p is involved in the hypoxia-induced endothelial-to-mesenchymal transition of neonatal pulmonary hypertension. Hypertens Res. 2017;40:552–61.
Arif M, Sadayappan S, Becker RC, Martin LJ, Urbina EM. Epigenetic modification: a regulatory mechanism in essential hypertension. Hypertens Res. 2019. https://doi.org/10.1038/s41440-019-0248-0
Bao X, Zheng S, Mao S, Gu T, Liu S, Sun J, et al. A potential risk factor of essential hypertension in case-control study: circular RNA hsa_circ_0037911. Biochem Biophys Res Commun. 2018;498:789–94.
Santhanam P, Khitan Z, Khthir R. Association between serum total bilirubin and serum creatinine and the effect of hypertension. J Clin Hypertens. 2015;17:61–62.
Zheng S, Gu T, Bao X, Sun J, Zhao J, Zhang T, et al. Circular RNA hsa_circ_0014243 may serve as a diagnostic biomarker for essential hypertension. Exp Ther Med. 2019;17:1728–36.
Wu N, Jin L, Cai J. Profiling and bioinformatics analyses reveal differential circular RNA expression in hypertensive patients. Clin Exp Hypertens. 2017;39:454–9.
Haque S, Harries LW. Circular RNAs (circRNAs) in health and disease. Genes. 2017;8:E353. https://doi.org/10.3390/genes8120353
Cheng X, Joe B. Circular RNAs in rat models of cardiovascular and renal diseases. Physiol Genom. 2017;49:484–90.
Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003;42:1149–60.
Liu C, Yao MD, Li CP, Shan K, Yang H, Wang JJ, et al. Silencing of circular RNA-ZNF609 ameliorates vascular endothelial dysfunction. Theranostics. 2017;7:2863–77.
Thompson AAR, Lawrie A. Targeting vascular remodeling to treat pulmonary arterial hypertension. Trends Mol Med. 2017;23:31–45.
Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493–537.
Wang J, Zhu MC, Kalionis B, Wu JZ, Wang LL, Ge HY, et al. Characteristics of circular RNA expression in lung tissues from mice with hypoxia‑induced pulmonary hypertension. Int J Mol Med. 2018;42:1353–66.
Madani M, Ogo T, Simonneau G. The changing landscape of chronic thromboembolic pulmonary hypertension management. Eur Respir Rev. 2017;26:170105. https://doi.org/10.1183/16000617.0105-2017
Pesavento R, Prandoni P. Prevention and treatment of the chronic thromboembolic pulmonary hypertension. Thromb Res. 2018;164:150–6.
Chen Z, Nakajima T, Tanabe N, Hinohara K, Sakao S, Kasahara Y, et al. Susceptibility to chronic thromboembolic pulmonary hypertension may be conferred by miR-759 via its targeted interaction with polymorphic fibrinogen alpha gene. Hum Genet. 2010;128:443–52.
Miao R, Wang Y, Wan J, Leng D, Gong J, Li J, et al. Microarray analysis and detection of micrornas associated with chronic thromboembolic pulmonary hypertension. Biomed Res Int. 2017;2017:8529796. https://doi.org/10.1155/2017/8529796
Miao R, Dong XB, Gong JN, Li JF, Pang WY, Liu YY, et al. Analysis of significant microRNA associated with chronic thromboembolic pulmonary hypertension. Zhonghua Yi Xue Za Zhi. 2018;98:1397–402.
Miao R, Wang Y, Wan J, Leng D, Gong J, Li J, et al. Microarray expression profile of circular RNAs in chronic thromboembolic pulmonary hypertension. Medicine 2017;96:e7354. https://doi.org/10.1097/MD.0000000000007354
Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM, Hofmeyr GJ. Pre-eclampsia. Lancet 2016;387:999–1011.
Phipps E, Prasanna D, Brima W, Jim B. Preeclampsia: updates in pathogenesis, definitions, and guidelines. Clin J Am Soc Nephrol. 2016;11:1102–13.
Moghaddas Sani H, Zununi Vahed S, Ardalan M. Preeclampsia: a close look at renal dysfunction. Biomed Pharm. 2018;109:408–16.
Song X, Luo X, Gao Q, Wang Y, Gao Q, Long W. Dysregulation of LncRNAs in placenta and pathogenesis of preeclampsia. Curr Drug Targets. 2017;18:1165–70.
Biró O, Nagy B, Rigó J Jr. Identifying miRNA regulatory mechanisms in preeclampsia by systems biology approaches. Hypertens Pregnancy. 2017;36:90–99.
Wu L, Zhou H, Lin H, Qi J, Zhu C, Gao Z, et al. Circulating microRNAs are elevated in plasma from severe preeclamptic pregnancies. Reproduction 2012;143:389–97.
Stubert J, Koczan D, Richter DU, Dieterich M, Ziems B, Thiesen HJ, et al. miRNA expression profiles determined in maternal sera of patients with HELLP syndrome. Hypertens Pregnancy. 2014;33:215–35.
Lv Y, Lu C, Ji X, Miao Z, Long W, Ding H, et al. Roles of microRNAs in preeclampsia. J Cell Physiol. 2019;234:1052–61.
Qian Y, Lu Y, Rui C, Qian Y, Cai M, Jia R. Potential significance of circular RNA in human placental tissue for patients with preeclampsia. Cell Physiol Biochem. 2016;39:1380–90.
Zhang YG, Yang HL, Long Y, Li WL. Circular RNA in blood corpuscles combined with plasma protein factor for early prediction of pre-eclampsia. BJOG. 2016;123:2113–8.
Jiang M, Lash GE, Zhao X, Long Y, Guo C, Yang H. CircRNA-0004904, CircRNA-0001855, and PAPP-A: potential novel biomarkers for the prediction of preeclampsia. Cell Physiol Biochem. 2018;46:2576–86.
Hu X, Ao J, Li X, Zhang H, Wu J, Cheng W. Competing endogenous RNA expression profiling in pre-eclampsia identifies hsa_circ_0036877 as a potential novel blood biomarker for early pre-eclampsia. Clin Epigenetics. 2018;10:48. https://doi.org/10.1186/s13148-018-0482-3
Zhou W, Wang H, Wu X, Long W, Zheng F, Kong J, et al. The profile analysis of circular RNAs in human placenta of preeclampsia. Exp Biol Med. 2018;0:1–9. https://doi.org/10.1177/1535370218813525
Zaiou M, El Amri H. Cardiovascular pharmacogenetics: a promise for genomically-guided therapy and personalized medicine. Clin Genet. 2017;91:355–70.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42:1206–52.
Kok MGM, de Ronde MWJ, Moerland PD, Ruijter JM, Creemers EE, Pinto-Sietsma SJ. Small sample sizes in high-throughput miRNA screens: a common pitfall for the identification of miRNA biomarkers. Biomol Detect Quantif. 2015;15:1–5.
Schober A, Nazari-Jahantigh M, Weber C. MicroRNA-mediated mechanisms of the cellular stress response in atherosclerosis. Nat Rev Cardiol. 2015;12:361–74.
Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature 2011;469:336–42.
Dang RY, Liu FL, Li Y. Circular RNA hsa_circ_0010729 regulates vascular endothelial cell proliferation and apoptosis by targeting the miR-186/HIF-1α axis. Biochem Biophys Res Commun. 2017;490:104–10.
Kramer H, Han C, Post W, Goff D, Diez-Roux A, Cooper R, et al. Racial/ethnic differences in hypertension and hypertension treatment and control in the multiethnic study of atherosclerosis (MESA). Am J Hypertens. 2004;17:963–70.
Cooper RS, Kaufman JS. Race and hypertension: science and nescience. Hypertension 1998;32:813–6.
Dluzen DF, Noren Hooten N, Zhang Y, Kim Y, Glover FE, Tajuddin SM, et al. Racial differences in microRNA and gene expression in hypertensive women. Sci Rep. 2016;6:35815. https://doi.org/10.1038/srep35815
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Zaiou, M. Circular RNAs in hypertension: challenges and clinical promise. Hypertens Res 42, 1653–1663 (2019). https://doi.org/10.1038/s41440-019-0294-7
- Circular RNAs (circRNAs)
- Pulmonary hypertension
- microRNAs (miRNAs)
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