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MiRNA expression analysis emphasized the role of miR-424 in diabetic cardiovascular complications

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International Journal of Diabetes in Developing Countries Aims and scope Submit manuscript

Abstract

Background

The discovery of miRNAs as promising new biomarkers in the field of cardiovascular disease has caused great expectations. Stability in the bloodstream, specific regulation, and high sensitivity and specificity suggest that the feasibility of miRNAs as cardiovascular biomarkers can even displace protein-based biomarkers. The objective of our study was to determine the plasma expression profile of miRNAs, which are reported to have important correlations with cardiovascular diseases, in patients with type 2 diabetes mellitus in relation to cardiovascular complications.

Methods

We isolated plasma miRNAs from 6 patients with type 2 diabetes mellitus without cardiovascular disease (control group) and 9 patients with type 2 diabetes mellitus and cardiovascular disease (target group). Following reverse transcription and subsequent real-time PCR analysis of the same amount of starting miRNAs, the following miRNAs were successfully analyzed: miR-16-5p, miR-155-3p, miR-155-5p, miR-210, miR-221-3p, and miR-424-5p.

Results

The relative expression analysis showed a statistically significant increase in the expression of all these miRNAs in the target group. The highest level of increase was established for miR-424-5p with an average relative quantification value of 10.5, followed by miR-155-5p with an average value of 7.5.

Conclusion

Cardiovascular risk assessment, supported by emerging circulating biomarkers, such as miRNAs, is important for stratifying high-risk individuals, optimizing treatment strategies, and enhancing our understanding of basic biology. Our study showed the highest increase in expression levels of miR-424-5p in target group and emphasized its role as a biomarker for cardiovascular damage in patients with type 2 diabetes mellitus.

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Availability of data and material

All data and material are available at the Molecular Medicine Centre, Medical University Sofia.

References

  1. Cho NHSJ, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, Malanda B. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–81.

    Article  CAS  Google Scholar 

  2. Bulugahapitiya U, Siyambalapitiya S, Sithole J, Idris I. Is diabetes a coronary risk equivalent? Systematic review and meta-analysis. Diabet Med. 2009;26:142–8.

    Article  CAS  Google Scholar 

  3. Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med. 2009;27:351–7.

    Article  CAS  Google Scholar 

  4. Cannell IG, Kong YW, Bushell M. How do microRNAs regulate gene expression? Biochem Soc Trans. 2008;36:1224–31.

    Article  CAS  Google Scholar 

  5. Ding Y, Sun X, Shan PF. MicroRNAs and cardiovascular disease in diabetes mellitus. Biomed Res Int. 2017;2017:1–8. https://doi.org/10.1155/2017/4080364.

    Article  CAS  Google Scholar 

  6. Thomas MR, Lip GY. Novel risk markers and risk assessments for cardiovascular disease. Circ Res. 2017;120:133–49.

    Article  CAS  Google Scholar 

  7. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105:10513–8.

    Article  CAS  Google Scholar 

  8. Jones Buie JN, Goodwin AJ, Cook JA, Halushka PV, Fan H. The role of miRNAs in cardiovascular disease risk factors. Atherosclerosis. 2016;254:271–81.

    Article  CAS  Google Scholar 

  9. Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A. 2011;108:5003–8.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. He Y, Ding Y, Liang B, et al. A systematic study of dysregulated microRNA in type 2 diabetes mellitus. In: Cho WC, editor. International journal of molecular sciences, 2017; 18(3): p. 456.

  12. Belgardt BF, Ahmed K, Spranger M, Latreille M, Denzler R, Kondratiuk N, et al. The microRNA-200 family regulates pancreatic b-cell survival in type 2 diabetes. Nat Med. 2015;21:619e27.

    Article  Google Scholar 

  13. Lin X, Guan H, Huang Z, Liu J, Li H, Wei G, et al. Downregulation of Bcl-2 expression by miR-34a mediates palmitate-induced Min6 cells apoptosis. J Diabetes Res. 2014;1729.

  14. Zhang W, Xie HY, Ding SM, Xing CY, Chen A, Lai MC, et al. CADM1 regulates the G1/S transition and represses tumorigenicity through the Rb-E2F pathway in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2016;15:289e96.

    Google Scholar 

  15. Zhu Y, You W, Wang H, Li Y, Qiao N, Shi Y, et al. MicroRNA-24/MODY generegulatory pathway mediates pancreatic b-cell dysfunction. Diabetes. 2013;62:3194e206.

    Google Scholar 

  16. Yang WM, Jeong HJ, Park SY, Lee W. Saturated fatty acid-induced miR-195 impairs insulin signaling and glycogen metabolism in HepG2 cells. FEBS Lett. 2014b;588:3939e46.

    Google Scholar 

  17. Nathan G, Kredo-Russo S, Geiger T, Lenz A, Kaspi H, Hornstein E, et al. MiR-375 promotes redifferentiation of adult human b-cells expanded in vitro. PLoS One. 2015;10:1729.

    Google Scholar 

  18. Shae A, Azarpira N, Karimi MH, Soleimani M, Dehghan S. Differentiation of human-induced pluripotent stem cells into insulin-producing clusters by microRNA-7. Exp Clin Transplant. 2015;16:121e8.

    Google Scholar 

  19. Gilbert ER, Liu D. Epigenetics: the missing link to understanding b-cell dysfunction in the pathogenesis of type 2 diabetes. Epigenetics. 2012;7:841e52.

    Article  Google Scholar 

  20. Plaisance V, Waeber G, Regazzi R, Abderrahmani A. Role of microRNAs in islet b-cell compensation and failure during diabetes. J Diabetes Res. 2014;2014:618652.

    PubMed  PubMed Central  Google Scholar 

  21. Williams MD, Mitchell GM. MicroRNAs in insulin resistance and obesity. Exp Diabetes Res. 2012;2012:484696.

    Article  Google Scholar 

  22. Nielsen S, Akerstrom T, Rinnov A, Yfanti C, Scheele C, Pedersen BK, et al. The miRNA plasma signature in response to acute aerobic exercise and endurance training. PLoS One. 2014;9:e87308.

    Article  Google Scholar 

  23. Cakmak HA, Barman HA, Ikitimur B, Coskunpinar E, Oltulu YM, Can G, et al. The assessment of relationship between dysregulated microRNAs and left ventricular mass and mass index in systolic heart failure. J Am Coll Cardiol. 2013;62:C17–C.

    Google Scholar 

  24. Ali SS, Kala C, Abid M, Ahmad N, Sharma US, Khan NA. Pathological microRNAs in acute cardiovascular diseases and microRNA therapeutics. J Acute Dis. 2016;5:9–1.

    Article  CAS  Google Scholar 

  25. Du F, Yu F, Wang Y, Hui Y, Carnevale K, Fu M, et al. MicroRNA-155 deficiency results in decreased macrophage inflammation and attenuated atherogenesis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2014;34:759–67.

    Article  CAS  Google Scholar 

  26. Jamaluddin MS, Weakley SM, Zhang L, Kougias P, Lin PH, Yao Q, et al. miRNAs: roles and clinical applications in vascular disease. Expert Rev Mol Diagn. 2011;11:79–89.

    Article  CAS  Google Scholar 

  27. Contu R, Latronico MV, Condorelli G. Circulating microRNAs as potential biomarkers of coronary artery disease: a promise to be fulfilled? Circ Res. 2010;107:573–4.

    Article  CAS  Google Scholar 

  28. Silva GJJ, Bye A, El Azzouzi H, Wisloff U. MicroRNAs as important regulators of exercise adaptation. Prog Cardiovasc Dis. 2017;60:130–51.

    Article  Google Scholar 

  29. Coskunpinar E, Cakmak HA, Kalkan AK, Tiryakioglu NO, Erturk M, Ongen Z. Circulating miR-221-3p as a novel marker for early prediction of acute myocardial infarction. Gene. 2016;591:90–6.

    Article  CAS  Google Scholar 

  30. Zhou Y, Richards AM, Wang P. MicroRNA-221 is cardioprotective and anti-fibrotic in a rat model of myocardial infarction. Molecular Therapy Nucleic Acids. 2019;17:185–97.

    Article  CAS  Google Scholar 

  31. Fasanaro P, D’Alessandra Y, Di Stefano V, Melchionna R, Romani S, Pompilio G, et al. MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J Biol Chem. 2008;283:15878–83.

    Article  CAS  Google Scholar 

  32. Pulkkinen K, Malm T, Turunen M, Koistinaho J, Yla-Herttuala S. Hypoxia induces microRNA miR-210 in vitro and in vivo ephrin-A3 and neuronal pentraxin 1 are potentially regulated by miR-210. FEBS Lett. 2008;582:2397–401.

    Article  CAS  Google Scholar 

  33. Bostjancic E, Zidar N, Glavac D. MicroRNA microarray expression profiling in human myocardial infarction. Dis Markers. 2009;27:255–68.

    Article  CAS  Google Scholar 

  34. Greco S, Fasanaro P, Castelvecchio S, D'Alessandra Y, Arcelli D, Di Donato M, et al. MicroRNA dysregulation in diabetic ischemic heart failure patients. Diabetes. 2012;61:1633–41.

    Article  CAS  Google Scholar 

  35. Sayed AS, Xia K, Li F, Deng X, Salma U, Li T, et al. The diagnostic value of circulating microRNAs for middle-aged (40-60-year-old) coronary artery disease patients. Clinics. 2015;70:257–63.

    Article  Google Scholar 

  36. Guan Y, Song X, Sun W, Wang Y, Liu B. Effect of Hypoxia-Induced MicroRNA-210 Expression on cardiovascular disease and the underlying mechanism. Oxidative Med Cell Longev. 2019;2019:4727283.

    Article  Google Scholar 

  37. Osipova J, Fischer DC, Dangwal S, Volkmann I, Widera C, Schwarz K, et al. Diabetes-associated microRNAs in pediatric patients with type 1 diabetes mellitus: a cross-sectional cohort study. J Clin Endocrinol Metab. 2014;99(9):E1661–5.

    Article  CAS  Google Scholar 

  38. Amr KS, Abdelmawgoud H, Ali ZY, Shehata S, Raslan HM. Potential value of circulating microRNA-126 and microRNA-210 as biomarkers for type 2 diabetes with coronary artery disease. Br J Biomed Sci. 2018;75(2):82–7.

    Article  CAS  Google Scholar 

  39. Ghosh G, Subramanian IV, Adhikari N, Zhang X, Joshi HP, Basi D, et al. Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis. J Clin Invest. 2010;120:4141–54.

    Article  CAS  Google Scholar 

  40. Kakimoto Y, Tanaka M, Hayashi H, Yokoyama K, Osawa M. Overexpression of miR-221 in sudden death with cardiac hypertrophy patients. Heliyon. 2018;4(6):e00639.

    Article  Google Scholar 

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Funding

The study was supported by the Grant of Bulgarian National Scientific Foundation with no. КП-06-Н 33/10, 2019.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Medical University Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria

    Ivelina Mihaleva, Rumen Nikolov, Tsvetanka Markova & Pavlina Gateva

  2. Molecular Medicine Center, Medical University Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria

    Silva Kyurkchiyan, Rumyana Dodova & Ivanka Dimova

  3. Department of Medical Genetics, Medical University Sofia, 2 Zdrave str., 1431, Sofia, Bulgaria

    Ivanka Dimova

Authors
  1. Ivelina Mihaleva
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  2. Silva Kyurkchiyan
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  3. Rumyana Dodova
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  4. Rumen Nikolov
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  5. Tsvetanka Markova
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  6. Pavlina Gateva
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  7. Ivanka Dimova
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Contributions

All authors contributed to the study conception and design. Methodology: Ivelina Mihaleva, Silva Kyurkchiyan, Rumyana Dodova, Ivanka Dimova. Formal analysis and investigation: Ivelina Mihaleva, Pavlina Gateva, Rumen Nikolov, Tsvetanka Markova, Ivanka Dimova. Writing—original draft preparation: Ivelina Mihaleva, Ivanka Dimova. Writing—review and editing: Pavlina Gateva, Rumen Nikolov, Tsvetanka Markova. Funding acquisition: Ivanka Dimova. Resources: Ivanka Dimova. Supervision: Ivanka Dimova

Corresponding author

Correspondence to Ivanka Dimova.

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Ethics approval

The collection of patients’ samples was approved by the institutional ethical committee (Medical University Sofia) with the approval no. 1209/2018. The research does not include animals.

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All participants in the study signed the informed consent before collection of the samples.

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It is included in the text of the informed consent signed by the patient.

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The authors declare that they have no conflict of interest.

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Mihaleva, I., Kyurkchiyan, S., Dodova, R. et al. MiRNA expression analysis emphasized the role of miR-424 in diabetic cardiovascular complications. Int J Diabetes Dev Ctries 41, 579–585 (2021). https://doi.org/10.1007/s13410-021-00934-8

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  • DOI: https://doi.org/10.1007/s13410-021-00934-8

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