ASSOCIATION OF MICRORNAS WITH CARDIOVASCULAR DISEASES IN TYPE 2 DIABETES MELLITUS

ASSOCIATION OF MICRORNAS WITH CARDIOVASCULAR DISEASES IN TYPE 2 DIABETES MELLITUS

Oksana Vengrzhinovskaya

clinical-in-training endocrinologist Endocrinology Research Centre,

Russia, Moscow

ABSTRACT

Diabetes mellitus type 2 is an epidemic of the 21st century, it disrupts all types of metabolism and leads to organ dysfunctions, in particular affecting the cardiovascular system. Cardiac complications are one of the most dangerous in type 2 diabetes. Despite the long years of studying the molecular genetic basis of the development of cardiovascular diseases, they still remain the subject of numerous studies. Recent studies indicate that microRNAs regulate 30% of all human genes, including genes responsible for the development and progression of cardiovascular diseases in type 2 diabetes. This review presents the results of studies on the role of microRNAs as epigenetic regulators in type 2 diabetes mellitus. And it has been shown that microRNAs are promising therapeutic targets for targeted therapy for CVD.

Keywords: genetics, microRNA, diabetic cardiomyopathy, cardiovascular diseases.

Introduction: Around the world, the number of patients with type 2 diabetes mellitus (DM-2) and cardiovascular diseases (CVD) is growing steadily. The prevalence of CVD leads to disability or premature death of patients with DM-2 [1]. Despite many years of studying the molecular genetic foundations of the development of these pathological conditions, their exact genesis has not yet been established. Probably, the pathological relationship of these is determined by individual molecular genetic factors. Recent studies show the involvement of microRNAs as dynamic regulators of the pathogenesis of CD-2 and CVD [2].

MicroRNAs are a separate class of RNA molecules that play a key role in the post-transcriptional regulation of gene expression [3]. MicroRNAs influence development, including endothelial dysfunction (DE), cell adhesion, and atherosclerotic plaque (ABP) formation [4]. Some microRNAs are considered as potential diagnostic markers of coronary heart disease (CHD) and acute myocardial infarction (AMI). MicroRNAs are detected in biological fluids, which makes them not only potential biomarkers for diagnosing and predicting the development of diseases, but also as macro markers of the effectiveness of CVD treatment. The functions of microRNAs are very diverse. A single microRNA can regulate hundreds of genes. This occurs through interaction with complementary regions located in the 3 ́-terminal untranslated sequences (3 ’UTR) of messenger RNA (mRNA) [5]. Many studies indicate differences in the expression of certain miRNAs in the plasma of patients with CD-2 in comparison with the control group of healthy patients [6]. Among human microRNAs, there are about 50, presumably associated with CVD [7].

Arterial hypertension (AH)

Arterial hypertension - Characterized by an increase in systolic blood pressure (BP)> 140 mm Hg. or diastolic blood pressure> 90 mmHg. Essential hypertension is idiopathic, its development is based on two main mechanisms: an increase in vascular tone and hyperactivation of the renin-angio-tensin-aldosterone system (RAAS). Increased activation of the RAAS is often determined in overweight individuals and with diabetes mellitus-2. It is believed that angiotensin II (AT II) plays an important role in the development of obesity and as a consequence of diabetes mellitus. Hi promotes the growth and differentiation of adipocytes, increases the synthesis, accumulation and absorption of fatty acids and slows down lipolysis [8]. AT II stimulates the growth of pre-adipocytes; affects the blood flow in adipose tissue inhibits lipolysis, stimulates lipogenesis, while reducing insulin-dependent glucose uptake, increases gluconeogenesis in the liver and glycogenolysis, which also leads to CD-2 [9]. The components of the RAAS, synthesized in adipose tissue, can also play a significant role in the development of hypertension. Average daily blood pressure levels and the activity of RAAS components (AT II, ​​plasma angiotensinogen) were higher in the group of rats with DM-2, compared with rats without DM [10].

The medial layer of arteries and veins is made up of smooth muscle cells (SMCs). Differentiated SMCs exhibit proliferative or contractile properties that affect vascular function under normal and pathological conditions. MicroRNAs regulate the development of vascular SMCs, as well as their functions in various CVDs [11].

Hyperlipidemia.

An increase in serum cholesterol and other lipids is called hyperlipidemia. In turn, there is another - dyslipidemia is an increase in the ratio of low density lipoproteins (LDL) to high density lipoproteins (HDL). These two disorders of lipid metabolism are a serious risk factor for the development of CVD [9]. For example, patients with elevated total cholesterol levels or elevated LDL cholesterol levels have a higher risk of developing coronary artery disease [4]. Many mechanisms affect lipid metabolism. The regulation of serum lipid levels also occurs with the participation of microRNA. Studies have shown that inhibition of microRNA-33a / b leads to an increase in total cholesterol concentration [12]. MicroRNA also has a positive effect on lipid metabolism: microRNA-122, which is expressed in the liver, has been shown in studies to reduce total cholesterol levels [13].

Atherosclerosis.

Atherosclerosis is a chronic disease of elastic and muscular-elastic arteries that occurs when lipid metabolism is disturbed and is accompanied by the deposition of cholesterol in the lumen of the vessels. Atherosclerosis occurs due to hyperglycemia, hyperlipidemia, and immune inflammation mediated by macrophages and lymphocytes [9].

An important stage in the development of atherosclerosis is the accumulation of cholesterol by macrophages. Under the influence of cytokines and vasoactive peptides (α-tumor necrosis factor and AT II), various adhesion molecules of leukocytes, mainly monocytes, on the endothelial surface are activated and their migration into the vascular wall begins. In the vascular wall, monocytes under the influence of macrophage colony-stimulating factor differentiate into macrophages, which capture modified lipoprotein particles. Macrophages form "foam" cells and release pro-inflammatory cytokines and growth factors.

MicroRNAs are involved and have a protective effect on blood vessels, preventing the development of atherosclerosis. The protective role of microRNA-21 in cardiomyocyte apoptosis, induced by ischemia in atherosclerosis and / or hypoxia in reperfusion, has been revealed [14]. Also, the expression of miRNA-21 is significantly increased in atherosclerotic plaques, therefore, suppressing the expression of this miRNA can slow down the development of atherosclerosis [15]. One of the studies revealed that the expression of miRNA-21 is significantly increased in macrophages in patients with unstable atherosclerotic plaques in comparison with that in patients with stable plaques or a control group. Therefore, the expression level of miRNA-21 can be used as a marker of atherosclerotic plaque instability [16].

Myocardial remodeling.

Remodeling of the myocardium leads to a decrease in ejection fraction and a decrease in the efficiency of blood circulation. CVDs of various origins have a common histological picture - - death of cardiomyocytes, due to compensatory pathological remodeling of the heart and reduced functional recovery. Myocardial remodeling is a widely studied problem. MicroRNAs are deeply involved in the processes of myocardial remodeling, and the effect on them may be one of the therapeutic targets for preventing the development or progression of HF [9].

MicroRNA-21 is the most studied in myocardial remodeling. Its expression is significantly increased with myocardial hypertrophy [17]. The use of pharmacological antagonists of miRNA-21 reduces myocardial hypertrophy and fibrosis, which leads to an improvement in cardiac function [18].

Conclusion:The main goal of therapy. diabetes mellitus is the prevention of complications. In type 2 diabetes mellitus, cardiovascular complications are the most dangerous. Timely diagnosis and prevention of their development will help improve the quality of life of patients and reduce the economic costs of the state for the treatment of such patients. The mechanisms presented in this review that affect the development of CVD in DM-2 only partially show the harmfulness of this effect. When screening patients with CD-2 for cardiovascular complications, they are detected in more than half of the patients. Earlier detection of these complications is necessary to improve the quality of life of patients with diabetes mellitus 2 and reduce the risk of premature death from CVD. Due to the high stability of microRNA in blood serum, these particles are new potential CVD biomarkers. Current studies have been conducted on relatively small patient samples, which is insufficient to study the full spectrum of microRNA action. A broader, accurate understanding of the functions of miRNAs as epigenetic regulators of CVD development in T2DM will allow the development of new therapeutic strategies.

References:

1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart Disease and Stroke Statistics-2014 Update: A Re- port From the American Heart Association. Circulation. 2013;129(3):e28-e292.
2. Avrahami D, Kaestner KH, editors. Epigenetic regulation of pan- creas development and function. Seminars in cell & developmen- tal biology; 2012: Elsevier.
3. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281-297. doi:10.1016/s00 92-8674(0 4)000 45-5
4. Nishiguchi T, Imanishi T, Akasaka T. MicroRNAs and cardiovascular diseases. BioMed Res Int. 2015;2015.
5. Weber JA, Baxter DH, Zhang S, Huang DY, How Huang K, Jen Lee M, et al. The MicroRNA Spectrum in 12 Body Fluids. Clin Chem. 2010;56(11):1733-1741. doi:10.1373/clinchem.2010.147405
6. Hoheisel JD, Wang X, Sundquist J, Zöller B, Memon AA, Palmér K et al. Determination of 14 Circulating microRNAs in Swedes and Iraqis with and without Diabetes Mellitus Type 2. PLoS ONE. 2014;9(1):e86792.
7. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433(7027):769-773. doi:10.1038/nature03315
8. Prognosis and Therapeutic Role of Circulating miRNAs in Cardiovascu- lar Diseases. Heart, Lung and Circulation. 2014;23(6):503-510. doi:10.1016/j.hlc.2014.01.001
9. Quiat D, Olson EN. MicroRNAs in cardiovascular disease: from pathogenesis to prevention and treatment. J Clin Invest. 2013;123(1):11-18. doi:10.1172/jci62876
10. Shestakova M.V. Activity of the renin-angiotensin system (RAS) of adipose tissue: metabolic effects of RAS blockade. Obesity and Metabolism. 2011; 8 (1): 21-25. DOI: 10.14341 / 2071-8713-5187
11. Ruhrberg C, Albinsson S, Skoura A, Yu J, DiLorenzo A, Fernán- dez-Hernando C, et al. Smooth Muscle miRNAs Are Critical for Post-Natal Regulation of Blood Pressure and Vascular Function. PLoS ONE. 2011;6(4):e18869. doi:10.1371/journal.pone.0018869
12. Rayner KJ, Suarez Y, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N et al. MiR-33 Contributes to the Regulation of Cholesterol Homeostasis. Science. 2010;328(5985):1570-1573. doi:10.1126/science.1189862
13. Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M et al. miR-122 regulation of lipid metabolism revealed by in vivo anti- sense targeting. Cell Metab. 2006;3(2):87-98. doi:10.1016/j.cmet.2006.01.005
14. Yang Q, Yang K, Li A. MicroRNA21 protects against ischemia reperfusion and hypoxia reperfusion induced cardiocyte apoptosis via the phosphatase and tensin homolog/aktdependent mecha- nism. Mol Med Rep. 2014;9:2213-22
15.  Raitoharju E, Lyytikäinen L-P, Levula M, Oksala N, Mennander A, Tarkka M, et al. miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study. Atherosclerosis. 2011;219(1):211-217. doi:10.1016/j.atherosclerosis.2011.07.020
16. Fan X, Wang E, Wang X, Cong X, Chen X. MicroRNA-21 is a unique signature associated with coronary plaque instability in hu- mans by regulating matrix metalloproteinase-9 via reversion-in- ducing cysteine-rich protein with Kazal motifs. Exper Molr Pathol. 2014;96(2):242-249. doi:10.1016/j.yexmp.2014.02.009
17. Van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J, Gerard RD et al. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proceedings of the National Academy of Sciences. 2006;103(48):18255-18260. doi:10.1073/pnas.0608791103
18. Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008;456(7224):980-984.  doi:10.1038/nature07511