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Circulating microRNA as a Novel Biomarker for Pulmonary Arterial Hypertension Due to Congenital Heart Disease

Pediatric Cardiology volume 38, pages 86–94 (2017)Cite this article

Abstract

Circulating microRNAs (miRNAs) have recently been indicated as practical and promising biomarkers for various diseases. However, circulating miRNAs have not been found to be biomarkers for pulmonary arterial hypertension (PAH) due to congenital heart disease. PAH is defined by a mean pulmonary arterial pressure (mPAP) >25 mmHg at rest. Blood samples and lung tissues were collected from patients with severe PAH due to ventricular septal defect (VSD) (PAH group, mPAP >45 mmHg, n=14) and patients with VSD but non-PAH (control group, mPAP <25 mmHg, n=16). Total RNA was extracted from the tissues and the plasma collected, and the different expression of miRNAs in tissues was detected by miRNA arrays. Selected miRNAs were also verified using real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Levels of miR-19a were quantified in the plasma of 30 patients. We also conducted receiver–operator characteristic curve analysis to evaluate the diagnostic ability of miR-19a; 78 microRNAs changed more than twofold. The changes in miR-19a, miR-130a, and miR-27b were also confirmed using qRT-PCR. miR-19a was then analyzed in prospectively collected plasma taken from both groups. The levels of miR-19a were significantly increased in the PAH samples. The value of the area under the receiver-operating characteristic curve was 0.781 (95% confidence interval, CI = 0.612–0.950, P < 0.0001) for the miR-19a assay. Circulating miR-19a turned out to be a pronounced marker for PAH. Our observations suggest that miR-19a expression is enhanced in PAH blood. Circulating miR-19a may be a novel biomarker for the diagnosis of PAH.

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References

  1. Humbert M, Sitbon O, Simonneau G (2004) Treatment of pulmonary arterial hypertension. N Engl J Med 351:1425–1436

    CAS  Article  PubMed  Google Scholar 

  2. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL et al (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105:10513–10518

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866

    CAS  Article  PubMed  Google Scholar 

  4. Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114

    CAS  Article  PubMed  Google Scholar 

  5. Olschewski H (2008) Dana Point: what is new in the diagnosis of pulmonary hypertension? Dtsch Med Wochenschr 133(Suppl 6):S180–S182

    Article  PubMed  Google Scholar 

  6. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108

    CAS  Article  PubMed  Google Scholar 

  7. Callis TE, Pandya K, Seok HY, Tang RH, Tatsuguchi M, Huang ZP et al (2009) MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest 119:2772–2786

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Sayed D, Hong C, Chen IY, Lypowy J, Abdellatif M (2007) MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res 100:416–424

    CAS  Article  PubMed  Google Scholar 

  9. Terentyev D, Belevych AE, Terentyeva R, Martin MM, Malana GE, Kuhn DE et al (2009) miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2. Circ Res 104:514–521

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN (2007) Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316:575–579

    Article  PubMed  Google Scholar 

  11. Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B et al (2007) The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med 13:486–491

    CAS  Article  PubMed  Google Scholar 

  12. Ai J, Zhang R, Li Y, Pu J, Lu Y, Jiao J et al (2010) Circulating microRNA-1 as a potential novel biomarker for acute myocardial infarction. Biochem Biophys Res Commun 391:73–77

    CAS  Article  PubMed  Google Scholar 

  13. Wang GK, Zhu JQ, Zhang JT, Li Q, Li Y, He J et al (2010) Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J 31:659–666

    Article  PubMed  Google Scholar 

  14. Tijsen AJ, Creemers EE, Moerland PD, de Windt LJ, van der Wal AC, Kok WE et al (2010) MiR423-5p as a circulating biomarker for heart failure. Circ Res 106:1035–1039

    CAS  Article  PubMed  Google Scholar 

  15. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thebaud B, Bonnet S et al (2006) An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation 113:2630–2641

    CAS  Article  PubMed  Google Scholar 

  16. Rabinovitch M (2008) Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 118:2372–2379

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Chen Y, Gorski DH (2008) Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5. Blood 111:1217–1226

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Kuehbacher A, Urbich C, Zeiher AM, Dimmeler S (2007) Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res 101:59–68

    CAS  Article  PubMed  Google Scholar 

  19. Chen T, Zhou G, Zhou Q, Tang H, Ibe JC, Cheng H, Gou D, Chen J, Yuan JX, Raj JU (2015) Loss of microrna-17 approximately 92 in smooth muscle cells attenuates experimental pulmonary hypertension via induction of pdz and lim domain 5. Am J Respir Crit Care Med 191:678–692

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Dews M, Homayouni A, Yu D, Murphy D, Sevignani C, Wentzel E et al (2006) Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet 38:1060–1065

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Zhang S, Fantozzi I, Tigno DD, Yi ES, Platoshyn O, Thistlethwaite PA et al (2003) Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 285:L740–L754

    CAS  Article  PubMed  Google Scholar 

  22. Brock M, Trenkmann M, Gay RE, Michel BA, Gay S, Fischler M et al (2009) Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ Res 104:1184–1191

    CAS  Article  PubMed  Google Scholar 

  23. Brun H, Holmstrom H, Thaulow E, Damas JK, Yndestad A, Aukrust P et al (2009) Patients with pulmonary hypertension related to congenital systemic-to-pulmonary shunts are characterized by inflammation involving endothelial cell activation and platelet-mediated inflammation. Congenit Heart Dis 4:153–159

    Article  PubMed  Google Scholar 

  24. Liu G, Friggeri A, Yang Y, Park YJ, Tsuruta Y, Abraham E (2009) miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses. Proc Natl Acad Sci U S A 106:15819–15824

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Venturini L, Battmer K, Castoldi M, Schultheis B, Hochhaus A, Muckenthaler MU et al (2007) Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells. Blood 109:4399–4405

    CAS  Article  PubMed  Google Scholar 

  26. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659

    CAS  Article  PubMed  Google Scholar 

  27. Tsujiura M, Ichikawa D, Komatsu S, Shiozaki A, Takeshita H, Kosuga T et al (2010) Circulating microRNAs in plasma of patients with gastric cancers. Br J Cancer 102:1174–1179

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by Science and Technology Planning of Guangzhou (2012IA011073).

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Affiliations

  1. Department of Cardiac Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, People’s Republic of China

    Weidan Chen

  2. Paediatric Cardiac Center, Department of Cardiac Surgery, Cardiovascular Institute & FuWai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, People’s Republic of China

    Shoujun Li

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  1. Weidan Chen
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  2. Shoujun Li
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Correspondence to Shoujun Li.

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Chen, W., Li, S. Circulating microRNA as a Novel Biomarker for Pulmonary Arterial Hypertension Due to Congenital Heart Disease. Pediatr Cardiol 38, 86–94 (2017). https://doi.org/10.1007/s00246-016-1487-3

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  • DOI: https://doi.org/10.1007/s00246-016-1487-3

Keywords

  • Congenital heart disease
  • microRNA
  • Pulmonary arterial hypertension