Circulating miсroRNAs in patients with ischemic heart disease with type 2 diabetes mellitus
DOI:
https://doi.org/10.14739/2310-1237.2020.3.221727Keywords:
coronary artery disease, type 2 diabetes mellitus, miсroRNAAbstract
The aim of the study was to investigate circulating miRNAs-27a, -221 levels and their relationship with glycemia and insulin resistance in patients with ischemic heart disease (IHD) with type 2 diabetes mellitus.
Materials and methods. The study included 58 patients with stable IHD with type 2 diabetes and 22 patients with IHD without diabetes. The control group consisted of 19 healthy persons. MicroRNAs-27a and -221 were determined in blood plasma by real time polymerase chain reaction. Small nuclear RNA U6 was used as endogenous control.
Results. In patients with IHD with diabetes circulating microRNAs27a and -221 levels were lower than in the controls (P = 0.024, P = 0.006, respectively) and in nondiabetic patients with IHD (P = 0.011, P = 0.001, respectively). In nondiabetic patients with IHD microRNAs-27a and 221 levels were nonsignificantly higher than in the controls (P > 0.05, for both). In diabetic patients with IHD the positive correlation between microRNAs (R = 0.319, P = 0.027) was significantly weaker than in the controls (R = 0.889, P < 0.001) (P < 0.001) and in nondiabetic patients with IHD (R = 0.772, P < 0.001) (P = 0.020). In patients with IHD with diabetes microRNA-27a negatively correlated with glycosylated hemoglobin (R = -0.339, P = 0.030), and microRNA-221 negatively correlated with the HOMA-IR (R = -0.362, P = 0.006). According to the ROC-analysis the decrease of both miRNAs levels was significantly associated with the presence of diabetes in patients with IHD. AUC for microRNA-27a was 0.692 (CI: 0.575–0.793, P = 0.009), AUC for microRNA-221 was 0.728 (CI: 0.617–0.821, P = 0.001).
Conclusions. In patients with IHD with type 2 diabetes mellitus circulating microRNAs-27a and -221 levels significantly decreased in comparison with both control and patients with IHD without diabetes. The decrease of microRNA-27a was associated with hyperglycemia, and the decrease of microRNA-221 was associated with the increase of insulin resistance. In patients with IHD without diabetes these microRNAs levels did not change.
References
- Einarson, T. R., Acs, A., Ludwig, C., & Panton, U. H. (2018). Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovascular diabetology, 17(1), 83. https://doi.org/10.1186/s12933-018-0728-6
- Emerging Risk Factors Collaboration, Sarwar, N., Gao, P., Seshasai, S. R., Gobin, R., Kaptoge, S., Di Angelantonio, E., Ingelsson, E., Lawlor, D. A., Selvin, E., Stampfer, M., Stehouwer, C. D., Lewington, S., Pennells, L., Thompson, A., Sattar, N., White, I. R., Ray, K. K., & Danesh, J. (2010). Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet, 375(9733), 2215-2222. https://doi.org/10.1016/S0140-6736(10)60484-9
- Naito, R., & Miyauchi, K. (2017). Coronary Artery Disease and Type 2 Diabetes Mellitus. International Heart Journal, 58(4), 475-480. https://doi.org/10.1536/ihj.17-191
- Santulli G. (2019). Editorial: Cardiovascular Disease and Diabetes. Frontiers in endocrinology, 10, 314. https://doi.org/10.3389/fendo.2019.00314
- De Rosa, S., Arcidiacono, B., Chiefari, E., Brunetti, A., Indolfi, C., & Foti, D. P. (2018). Type 2 Diabetes Mellitus and Cardiovascular Disease: Genetic and Epigenetic Links. Frontiers in endocrinology, 9, 2. https://doi.org/10.3389/fendo.2018.00002
- Das, A., Samidurai, A., & Salloum, F. N. (2018). Deciphering Non-coding RNAs in Cardiovascular Health and Disease. Frontiers in cardiovascular medicine, 5, 73. https://doi.org/10.3389/fcvm.2018.00073
- Çakmak, H. A., & Demir, M. (2020). MicroRNA and Cardiovascular Diseases. Balkan medical journal, 37(2), 60-71. https://doi.org/10.4274/balkanmedj.galenos.2020.2020.1.94
- Friedman, R. C., Farh, K. K., Burge, C. B., & Bartel, D. P. (2009). Most mammalian mRNAs are conserved targets of microRNAs. Genome research, 19(1), 92-105. https://doi.org/10.1101/gr.082701.108
- Kozomara, A., Birgaoanu, M., & Griffiths-Jones, S. (2019). miRBase: from microRNA sequences to function. Nucleic acids research, 47(D1), D155-D162. https://doi.org/10.1093/nar/gky1141
- O'Brien, J., Hayder, H., Zayed, Y., & Peng, C. (2018). Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Frontiers in endocrinology, 9, 402. https://doi.org/10.3389/fendo.2018.00402
- Chen, W. J., Yin, K., Zhao, G. J., Fu, Y. C., & Tang, C. K. (2012). The magic and mystery of microRNA-27 in atherosclerosis. Atherosclerosis, 222(2), 314-323. https://doi.org/10.1016/j.atherosclerosis.2012.01.020
- Chistiakov, D. A., Sobenin, I. A., Orekhov, A. N., & Bobryshev, Y. V. (2015). Human miR-221/222 in Physiological and Atherosclerotic Vascular Remodeling. BioMed research international, 2015, 1-18. https://doi.org/10.1155/2015/354517
- Chen, T., Zhang, Y., Liu, Y., Zhu, D., Yu, J., Li, G., Sun, Z., Wang, W., Jiang, H., & Hong, Z. (2019). MiR-27a promotes insulin resistance and mediates glucose metabolism by targeting PPAR-γ-mediated PI3K/AKT signaling. Aging, 11(18), 7510-7524. https://doi.org/10.18632/aging.102263
- Huang, F., Chen, J., Wang, J., Zhu, P., & Lin, W. (2019). Palmitic Acid Induces MicroRNA-221 Expression to Decrease Glucose Uptake in HepG2 Cells via the PI3K/AKT/GLUT4 Pathway. BioMed research international, 2019, 8171989. https://doi.org/10.1155/2019/8171989
- Fichtlscherer, S., De Rosa, S., Fox, H., Schwietz, T., Fischer, A., Liebetrau, C., Weber, M., Hamm, C. W., Röxe, T., Müller-Ardogan, M., Bonauer, A., Zeiher, A. M., & Dimmeler, S. (2010). Circulating microRNAs in patients with coronary artery disease. Circulation research, 107(5), 677-684. https://doi.org/10.1161/CIRCRESAHA.109.215566
- Draganova, A. S., Polyakova, E. A., Kolodina, D. A., Mikheeva, K. Yu., Belyaeva, O. D., Zaraysky, M. I., Berkovich, O. A., & Shlyakhto, E. V. (2019). Expression of miRNA-27a in the serum of patients with non-ST elevation acute coronary syndrome who underwent percutaneous coronary intervention. Russian Journal of Cardiology, (2), 70-75. https://doi.org/10.15829/1560-4071-2019-2-70-75
- Karolina, D. S., Tavintharan, S., Armugam, A., Sepramaniam, S., Pek, S. L., Wong, M. T., Lim, S. C., Sum, C. F., & Jeyaseelan, K. (2012). Circulating miRNA profiles in patients with metabolic syndrome. The Journal of clinical endocrinology and metabolism, 97(12), E2271-E2276. https://doi.org/10.1210/jc.2012-1996
- de Candia, P., Spinetti, G., Specchia, C., Sangalli, E., La Sala, L., Uccellatore, A., Lupini, S., Genovese, S., Matarese, G., & Ceriello, A. (2017). A unique plasma microRNA profile defines type 2 diabetes progression. PloS one, 12(12), e0188980. https://doi.org/10.1371/journal.pone.0188980
- Shvangiradze, T., Bondarenko, I., Troshina, E., Shestakova, M., Ilyin, A., Nikankina, L., Karpukhin, A., Muzaffarova, T., Kipkeeva, F., Grishina, K., & Kuzevanova, A. (2016). Profil mikroRNK, assotsiirovannykh s IBS, u patsientov s sakharnym diabetom 2 tipa [Profile of microRNAs associated with coronary heart disease in patients with type 2 diabetes]. Obesity and Metabolism, 13(4), 34-38. [in Russian].
- Yilmaz, S., Isbir, S., Kunt, A., & Isbir, T. Circulating microRNAs as Novel Biomarkers for Atherosclerosis. (2018). In Vivo, 32(3), 561-565. https://doi.org/10.21873/invivo.11276
- Liu, H. N., Li, X., Wu, N., Tong, M. M., Chen, S., Zhu, S. S., Qian, W., & Chen, X. L. (2018). Serum microRNA-221 as a biomarker for diabetic retinopathy in patients associated with type 2 diabetes. International journal of ophthalmology, 11(12), 1889-1894. https://doi.org/10.18240/ijo.2018.12.02
- Xie, W., Li, L., Zhang, M., Cheng, H., Gong, D., Lv, Y., … Tang, C. K. (2016). MicroRNA-27 Prevents Atherosclerosis by Suppressing Lipoprotein Lipase-Induced Lipid Accumulation and Inflammatory Response in Apolipoprotein E Knockout Mice. PloS one, 11(6), e0157085. https://doi.org/10.1371/journal.pone.0157085
- Yu Y., Du H., Wei S., Feng L., Li J., Yao F., Zhang M., Hatch G. M., & Chen L. (2018). Adipocyte-Derived Exosomal MiR-27a Induces Insulin Resistance in Skeletal Muscle Through Repression of PPARγ. Theranostics, 8(8), 2171-2188. https://doi.org/10.7150/thno.22565
- Wang, S., Ai, H., Liu, L., Zhang, X., Gao, F., Zheng, L., Yi, J., Sun, L., Yu, C., Zhao, H., & Li, Y. (2019). Micro-RNA-27a/b negatively regulates hepatic gluconeogenesis by targeting FOXO1. American journal of physiology. Endocrinology and metabolism, 317(5), E911-E924. https://doi.org/10.1152/ajpendo.00190.2019
- Ye, J., Wu, Y., Guo, R., Zeng, W., Duan, Y., Yang, Z., & Yang, L. (2019). miR-221 Alleviates the Ox-LDL-Induced Macrophage Inflammatory Response via the Inhibition of DNMT3b-Mediated NCoR Promoter Methylation. Mediators of inflammation, 2019, 4530534. https://doi.org/10.1155/2019/4530534
- Chen, C. F., Huang, J., Li, H., Zhang, C., Huang, X., Tong, G., & Xu, Y. Z. (2015). MicroRNA-221 regulates endothelial nitric oxide production and inflammatory response by targeting adiponectin receptor 1. Gene, 565(2), 246-251. https://doi.org/10.1016/j.gene.2015.04.014
- Deiuliis J. A. (2016). MicroRNAs as regulators of metabolic disease: pathophysiologic significance and emerging role as biomarkers and therapeutics. International journal of obesity, 40(1), 88-101. https://doi.org/10.1038/ijo.2015.170
- Peng, J., Zhou, Y., Deng, Z., Zhang, H., Wu, Y., Song, T., Yang, Y., Wei, H., & Peng, J. (2018). miR-221 negatively regulates inflammation and insulin sensitivity in white adipose tissue by repression of sirtuin-1 (SIRT1). Journal of cellular biochemistry, 119(8), 6418-6428. https://doi.org/10.1002/jcb.26589
- Vegter, E. L., Ovchinnikova, E. S., van Veldhuisen, D. J., Jaarsma, T., Berezikov, E., van der Meer, P., & Voors, A. A. (2017). Low circulating microRNA levels in heart failure patients are associated with atherosclerotic disease and cardiovascular-related rehospitalizations. Clinical research in cardiology : official journal of the German Cardiac Society, 106(8), 598-609. https://doi.org/10.1007/s00392-017-1096-z
- Togliatto, G., Trombetta, A., Dentelli, P., Rosso, A., & Brizzi, M. F. (2011). MIR221/MIR222-driven post-transcriptional regulation of P27KIP1 and P57KIP2 is crucial for high-glucose- and AGE-mediated vascular cell damage. Diabetologia, 54(7), 1930. https://doi.org/10.1007/s00125-011-2125-5
- Granjon, A., Gustin, M. P., Rieusset, J., Lefai, E., Meugnier, E., Güller, I., Cerutti, C., Paultre, C., Disse, E., Rabasa-Lhoret, R., Laville, M., Vidal, H., & Rome, S. (2009). The microRNA signature in response to insulin reveals its implication in the transcriptional action of insulin in human skeletal muscle and the role of a sterol regulatory element-binding protein-1c/myocyte enhancer factor 2C pathway. Diabetes, 58(11), 2555-2564. https://doi.org/10.2337/db09-0165
- Bildirici, A. E., Arslan, S., Özbilüm Şahin, N., Berkan, Ö., Beton, O., & Yilmaz, M. B. (2018). MicroRNA-221/222 expression in atherosclerotic coronary artery plaque versus internal mammarian artery and in peripheral blood samples. Biomarkers, 23(7), 670-675. https://doi.org/10.1080/1354750X.2018.1474260
- Karolina, D. S., Armugam, A., Tavintharan, S., Wong, M. T., Lim, S. C., Sum, C. F., & Jeyaseelan, K. (2011). MicroRNA 144 impairs insulin signaling by inhibiting the expression of insulin receptor substrate 1 in type 2 diabetes mellitus. PloS one, 6(8), e22839. https://doi.org/10.1371/journal.pone.0022839
- Nunez Lopez, Y. O., Garufi, G., & Seyhan, A. A. (2016). Altered levels of circulating cytokines and microRNAs in lean and obese individuals with prediabetes and type 2 diabetes. Molecular bioSystems, 13(1), 106-121. https://doi.org/10.1039/c6mb00596a
- Jia, Q. W., Chen, Z. H., Ding, X. Q., Liu, J. Y., Ge, P. C., An, F. H., Li, L. H., Wang, L. S., Ma, W. Z., Yang, Z. J., & Jia, E. Z. (2017). Predictive Effects of Circulating miR-221, miR-130a and miR-155 for Coronary Heart Disease: A Multi-Ethnic Study in China. Cellular physiology and biochemistry, 42(2), 808-823. https://doi.org/10.1159/000478071
- Ding, X. Q., Ge, P. C., Liu, Z., Jia, H., Chen, X., An, F. H., … Jia, E. Z. (2015). Interaction between microRNA expression and classical risk factors in the risk of coronary heart disease. Scientific reports, 5, 14925. https://doi.org/10.1038/srep14925
- Li, M. Y., Pan, S. R., & Qiu, A. Y. (2016). Roles of microRNA-221/222 in type 2 diabetic patients with post-menopausal breast cancer. Genetics and molecular research: GMR, 15(2), 10.4238/gmr.15027259. https://doi.org/10.4238/gmr.15027259
- Mononen, N., Lyytikäinen, L., Seppälä, I., Mishra, P., Juonala, M., Waldenberger, M. … Raitoharju, E. (2019). Whole blood microRNA levels associate with glycemic status and correlate with target mRNAs in pathways important to type 2 diabetes. Scientific Reports, 9(1), 8887. https://doi.org/10.1038/s41598-019-43793-4
- Stępień, E., Durak-Kozica, M., Kamińska, A., Targosz-Korecka, M., Libera, M., Tylko, G. … Enguita, F. J. (2018). Circulating ectosomes: Determination of angiogenic microRNAs in type 2 diabetes. Theranostics, 8(14), 3874-3890. https://doi.org/10.7150/thno.23334
- Viereck, J., & Thum, T. (2017). Circulating Noncoding RNAs as Biomarkers of Cardiovascular Disease and Injury. Circulation research, 120(2), 381-399. https://doi.org/10.1161/CIRCRESAHA.116.308434
Downloads
How to Cite
Issue
Section
License
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.





