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EPIGENETIC MECHANISMS OF ATHEROSCLEROSIS ETIOPATHOGENESIS
R.N. Mustafin*
Bashkir State Medical University, 3 Lenin St., Ufa, 450008, Russia. * Corresponding author: ruji79@mail.ru
Abstract. Epigenetic regulation of spatiotemporal gene expression in ontogenesis is determined by programmed species-specific activations of retroelements in successive cell divisions. Evolutionary selection of this genome control mechanism is aimed at achieving a mature state, after which unprogrammed activation of retroelements occurs, which expression products stimulate interferon response, aseptic inflammation and aging-associated diseases development, such as atherosclerosis. Interferon in atherosclerosis stimulates pro-inflammatory macrophage phenotype, which contributes to pathological immune response, foam cell formation and atherosclerosis progression. Activation of retroelements occurs under the influence of viral infections, which role in atherosclerosis development has been proven, which confirms my hypothesis. Dysfunctional foam macrophages produce HERV-K102, which stimulates innate immunity, HERV-K HML2 expression correlates with macrophage immune activation and interferon response. Data were obtained on association with atherosclerosis of microRNAs derived from retroelements, which are involved in the disease pathogenesis due to their influence on cholesterol metabolism (miR-498, -520d), immune processes (miR-1257, -28, -2909), activation of DNMT1 (miR-1264) and EZH2 (miR-630), gene expression in endothelial cells (10 specific miRNAs), vascular smooth muscle cells (14 specific miRNAs) and macrophages (miR-320b, -326, -378, -384), contributing to pathological phenotype of these cells. In atherosclerosis microRNAs derived from retroelements interact with circular RNAs (miR-495, -576, -579, -630, -633, -637, -942) and long non-coding RNAs (miR-326, -4731, -495, - 616, -641, -664a) the key sources of which are retroelements. Role of ANRIL, NEAT1, PAPIA, MAARS, VINAS, H19, AK136714, MIAT, and interaction of Alu elements with ANRIL and NEAT1, identified in atherosclerosis development. The data obtained can become the basis for targeted effect on retroelements activation in atherosclerosis using mi-croRNAs.
Keywords: atherosclerosis, epigenetic factors, long noncoding RNAs, microRNA, retroelements.
List of Abbreviations
AS - atherosclerosis ECs - endotheliocytes IFN - interferon
lncRNAs - long noncoding RNAs
ncRNAs - noncoding RNAs
REs - retroelements
TF - transcription factor
VSMCs - vascular smooth muscle cells
Introduction
Aging-associated inflammation of vessel walls plays an important role in the development of atherosclerosis (AS) (Franceschi et al., 2000; Menghini et al., 2014; de Yebenes et al., 2020). At the same time, during aging, pathological activation of HERV retroelements (REs) (Autio et al., 2020) and LINE-1 (Cardelli, 2018) occurs in all people. Retroele-ment expression products stimulate interferon (IFN) overproduction, promoting chronic aseptic inflammation (De Cecco et al., 2019; Autio
et al., 2020). REs belong to transposons, the movement of which occurs by reverse transcription of their RNA with insertion of the resulting cDNA into a new genomic locus (Cardelli, 2018). They occupy at least 45% of the human genome (Mustafin & Khusnutdi-nova, 2017).
The role of REs in the initiation and development of AS is due not only to IFN-mediated inflammation, but also to the participation of REs in the functioning of the immune system. This is evidenced by the emergence of RAG1 and RAG2, necessary for V(D)J recombination, from transposons (Huang et al., 2016). In addition, ERVs are used as enhancers of HLA-G genes (Chuong et al., 2018) and IFN-inducible genes (forming IFN response transcriptional networks (Chuong et al., 2016)). Meta-analyses have shown the role of RE dysregulation in autoimmune pathology (de la Hera et al., 2013), with which AS is reliably associated (Martinez-Ceballos et al., 2021).
AS is characterized by persistent inflammation due to disproportionate polarization of AS-associated macrophages from anti-inflammatory (M2-like) to pro-inflammatory (M1-like) under the influence of epigenetic factors (Yang et al., 2022). HERV-K102 is expressed by activated monocytes and is released into vacuoles associated with their surfaces, turning the cells into "foam cells." Release of HERV-K102 occurs only upon lysis of macrophages. At the same time, HERV-K102 protect human cells from viral infections and malignant neoplasms (Laderoute, 2020). Clinical studies have shown the role of viruses: (HIV (Freiberg et al., 2013), herpes simplex HSV-1 and HSV-2 (Wu et al.,
2016), hepatitis C (Olubamwo et al., 2016) and B (Rivero-Barciela et al., 2021), cytomegalovirus (Jia et al., 2017), influenza (Peretz et al., 2019)), in the development of AS. Therefore, overproduction of HERV-K102 as a protective mechanism against infections (Badarinarayan & Sauter, 2021) may contribute to impaired gene expression in macrophages and the development of AS (Chai et al., 2018).
REs serve as regulators of gene expression in human ontogenesis, being drivers of epige-netic regulation (Mustafin & Khusnutdinova,
2017), since they serve as sources of non-coding RNAs (ncRNAs), such as microRNAs (Wei et al., 2016) and long ncRNAs (lncRNAs) (Johnson, Gugo, 2014). Moreover, HERVs (Lu et al., 2014) and LINE-1s (Honson & Macfar-lan, 2018) can serve as direct ncRNA genes, as they are transcribed into functional lncRNAs involved in the regulation of ontogenesis. Therefore, changes in the expression of specific ncRNAs and epigenetic factors in AS may reflect dysregulation of REs.
Epigenetic factors of atherosclerosis development
The main epigenetic factors include DNA methylation, histone modifications, and RNA interference with ncRNA. At the same time, ncRNAs are not only involved in the post-tran-scriptional regulation of gene expression, but are also key drivers of DNA and histone modifications (Mustafin & Khusnutdinova, 2017) due to the mechanism of RNA-directed DNA
methylation (Chalertpet et al., 2019). DNA methylation is carried out by DNA methyltrans-ferase enzymes DNMT1, DNMT3a, DNMT3b, DNA demethylation is performed by Tet-methylcytosine dioxygenases TET1, TET2, TET3, acetylation of histones is carried out by acetyltransferases (HATs) (Xu et al., 2018). Histone deacetylases (HDAC) are classified into Class I (HDAC core enzymes-1, -2, -3, -8), Class II (HDAC-4, -5, -6, -7, -9, -10), III (sirtuins 1-7), IV (HDAC-11). Various HDACs are influenced by both microRNAs (for example, miR-34a (Li et al., 2018)) and transcription factors (TF), regulating their effect on gene expression (Lee et al., 2019).
In evolution, TFs (Feschotte, 2008) and binding sites for them (Mustafin, 2019), as well as microRNAs (Wei et al., 2016), arose from transposons, which indicates the mechanisms of their influence on epigenetic regulation. Changes in modifications of DNMT1/3a/3b, TET1/2/3, HAT and HDAC in the development of AS are described in a systematic review (Xu et al., 2018). An important role is played by changes in epigenetic regulation in the polarization of macrophages into M1-like macrophages under the influence of HDAC3, HDAC7, HDAC9 and H3K9/36me3 modifications (Yang et al., 2022a).
Changes in microRNA expression are described as pathogenetic factors of aging-developing AS (Menghini et al., 2014; de Yebenes et al., 2020). The role of microRNAs in the path-ogenesis of AS is due to various mechanisms, including the regulation of lipid metabolism and inflammation (Arora et al., 2014), and the aging of endotheliocytes (ECs) themselves. Inflammation in atherosclerosis is associated with elevated levels of miR-126, miR-221/222 and low levels of miR10a, miR-155, miR-181a, miR-221/222, which leads to apoptosis, cell cycle arrest, and the production of reactive oxygen species. With aging of the endothelium, there is an increase in the expression of miR-217, miR-34; a decrease in the production of miR-92a, miR-216a, which is accompanied by an increase in VCAM (vascular cell adhesion protein), ICAM (intercellular adhesion molecule), MCP1 (monocyte chemoattractant protein 1),
CXCL12 (chemokine (C-X-C motif) ligand 12) concentrations (Menghini et al., 2014). In addition to miR-34a and miR-217, miR-146a (Deng et al., 2017) and miR-200c (in response to reactive oxygen species) are associated with EC aging (Novak et al., 2017). Aging-associated miR-217 has been implicated in the development of AS and cardiovascular dysfunction by suppressing a network of activators of endothelial nitric oxide synthetases, including VEGF and apelin receptor pathways (de Yebenes et al., 2020). Inhibition of miR-34a, which promotes the development of AS, prevents cell apoptosis, contributing to their viability (Li et al., 2018).
A systematic review of the scientific literature conducted in 2018 showed that miR-19a, miR-19b, and miR-21 control inflammation of the vascular wall by regulating its infiltration by leukocytes and their activation. The key in the mechanisms of AS is miR-126, which inhibits VCAM-1 and proinflammatory TNF-a. Reduced expression of miR-126 activates NF-kB with increased interactions of leukocytes with endothelial cells and the development of AS. The influence on vascular smooth muscle cells (VSMCs) in the pathogenesis of AS is characterized by miR-1 (targets are mRNA of the KLF4, PIM1 genes), miR10a (target is HDAC4 mRNA), miR-126 (targets are BCL2, IRS1, FOXO3 mRNA), miR-22 (inhibits the MECP2, HDAC4, EVI1 genes), miR-143 and miR-145 (affect the ACE, ELK1, KLF4/5 genes), miR-21 (DOCK, PDCD4 genes are targets), miR-26a, miR- 34a, miR-130a, miR-221. Abnormal proliferation and migration of VSMCs are involved in neointimal formation and contributes to AS and restenosis (Chen et al., 2018).
Inflammatory macrophages secrete vesicles containing specific RNAs (miR-28, miR-146a, miR-185, miR-365, miR-503) that are used to communicate with cells of atherosclerotic vessels (Lu et al., 2018). Among circulating microRNAs specific for AS are miR-17, miR-17-5p, miR-29b, miR-30, miR-92a, miR-126, miR-143, miR-145, miR-146a, miR-212, miR -218, miR-221, miR-222 and miR-361-5p, which have been proposed as biomarkers for disease diagnosis (Sharma et al., 2022). MiR-
33, which regulates ABCA1 (ATP-binding cassette transporter A1)-dependent cholesterol efflux, influences the function of macrophages in AS. miR-33 also inhibits TFEB and FOXO3, reducing lysosomal activity and phagocytosis of macrophages. Therefore, exposure to anti-miR-33 increases efferocytosis, lysosomal biogenesis, and degradation of apoptotic material in macrophages. In experiments with Ldlr-/-mice with AS, anti-miR-33 restored defective autophagy in macrophage foam cells in plaques, promoting clearance of apoptotic cells and reducing plaque necrosis (Ouimet et al., 2017).
Relationship between long ncRNAs and retroelements in atherosclerosis
The observed changes in lncRNA levels in the pathogenesis of AS may be a reflection of the expression characteristics of RE, which serve as sources of ncRNAs (Wei et al., 2016; Johnson, Gugo, 2014; Lu et al., 2014; Honson & Macfarlan, 2018). In addition to the emergence of lncRNAs from retroelements (Johnson and Gugo, 2014) and their direct processing of mRNA from RE genes (Lu et al., 2014; Honson & Macfarlan, 2018), the role of interactions of RE with lncRNAs in the pathogenesis of AS has been described. Alu elements (belonging to non-autonomous RE) bind to lncRNA ANRIL, involved in the development of AS (Hueso et al., 2018). In turn, ANRIL interacts directly with Alu sequences in the genome (Chi et al., 2017), which have a proatherogenic effect, as they are located in the promoter regions of target genes (Holdt et al., 2013), such as those encoding proteins of the PRC-1 and PRC-2 groups. ANRIL recruits these proteins used for epigenetic modification of chromatin and inhibition of gene expression in cis-regulation of apoptosis, cell proliferation and adhesion, inflammation and AS development (Chi et al., 2017). In atherosclerosis, lncRNA RAPIA is expressed by macrophages, stimulating their proliferation and suppressing apoptosis. Inhibition of RAPIA in vivo suppresses the progression of AS and has an antiatherogenic effect (Sun et al. , 2020). Expression of the macro-phage-specific lncRNA MAARS in the aortic
intima increases 270-fold with AS progression and decreases by 60% with regression. In experiments on LDLR-/- mice, knockdown of MAARS reduced the formation of AS plaques by 52% due to a decrease in inflammation, macrophage apoptosis and an increase in efferocy-tosis in the vessel walls (Simion et al., 2020).
LncRNAs VINAS (Simon et al., 2020) and H19 (Pan, 2017) regulate MAPK and NF-kB signaling pathways involved in inflammation. Knockdown of VINAS reduces the expression of key inflammatory markers such as MCP-1, COX-2, TNF-a, IL-1P in endothelial cells (Simon et al. , 2020). In the blood plasma and plaques of patients with AS, an increased level of lncRNA AK136714 was detected, the inhibition of which suppresses AS and inflammation of endothelial cells. AK136714 enhances Bim transcription, directly binds to HuR, increasing the stability of TNF-a, IL-1P and IL-6 mRNA (Bai et al., 2021). The expression of the myo-cardial infarction-associated lncRNA MIAT is significantly increased in the serum of AS patients with unstable plaques. MIAT acts as a sponge for miR-149-5p by stimulating the antiphagocytic molecule CD47 (Ye et al., 2019).
Macrophages are characterized by the expression of autonomous REs, which can function as direct sources of lncRNAs (Lu et al., 2014). HERV-K HML-2 expression correlates with macrophage immune activation (polarization in M1) and response to IFNI (Russ et al., 2023). According to a new paradigm of im-munosenescence, dysfunctional (LB-) foamy macrophages (CD14+CD16+) produce HERV-K102 particles released to stimulate the trained innate immune system (Laderoute, 2020). Macrophages are also characterized by the expression of the ERVPbl gene, which is derived from the Env gene of HERV-P (Matsuzawa et al., 2021). The RNA molecule of Alu elements modified by adenosine-inosine editing controls the stability of the pro-inflammatory lncRNA NEAT1 in AS. NEAT1 expression, induced by TNF-a, is more than 2 times higher in blood monocytes of patients with coronary artery AS. Suppression of NEAT1 leads to attenuation of TNF-a-induced pro-inflammatory response of endothelial cells, as manifested by the expres-
sion of CXCL8, CCL2, VCAM1 and ICAM1 (Vlachogiannis et al., 2021).
The relationship between microRNA and retroelements in atherosclerosis
REs are the evolutionary sources of many microRNAs. According to the MDTE DB database, in humans, 661 miRNAs originate from transposons, mainly from REs (Wei et al., 2016). They can have both pro-atherogenic (increased concentration in patients with AS) and anti-atherogenic (low expression) effects, and participate in the pathogenesis of AS in various ways (Table 1). MicroRNA expression is determined both in patients with AS (for example, miR-1253, miR-1202 and many others) and in animal experiments (miR-31 (Liu et al., 2015b), miR-320b (Lu et al., 2022), miR-630 (Mia et al., 2022)). In patients with AS, the levels of these molecules are determined in blood plasma exosomes (miR-1202 (Sorrentino et al.,
2020)) or macrophages (miR-1271 (Long et al.,
2021)), coronary artery samples (miR-1273 (Wang et al., 2021) al., 2015)), in plasma (miR-1296, miR-493 (Niu et al., 2021), miR-335 (Hildebrandt et al., 2021)) and serum (miR-211 (Zhang et al., 2021), miR-3646 (Fan et al., 2020), miR-374 (Wang et al., 2020a), miR-502 (Wang et al., 2014), miR-582 (Hildebrandt et al., 2021)), in vascular smooth muscle cells (miR-421 (Yang et al., 2020)), in peripheral mononuclear cells (miR-2909 (Arora et al., 2014), miR-342 (Ahmadi et al., 2018)) and in adipose tissue around coronary arteries (miR-548 (Konwerski et al., 2021)).
Pathological proliferation, apoptosis, invasion and differentiation of VSMCs contribute to plaque formation in AS. In this case, VSMCs can transform into less differentiated forms that lack VSMC markers, including macrophage-like cells, which contribute to the progression of AS and inflammation (Bennett et al., 2016). This process is influenced by miR-1246 (Pan et al., 2021), miR-1253 (Wang et al., 2020b), miR-1278 (Ma et al., 2023), miR-192 (Zhao et al., 2021), miR-374 (Wang et al., 2020a), miR-4459 (Lin et al., 2022), miR-4487 (путем целевого воздействия на RASA1 (Liang et al.,
2022)), miR-4731 (взаимодействуя с FOXO3)
Table 1
Association of transposon-derived microRNAs with atherosclerosis
№ MicroRNA Transposon-source MicroRNA expression (increase - t, decrease - 1) Author
1. miR-1202 LTR-ERV1 t (Sorrentino et al., 2020)
2. miR-1246 LTR-ERVL t (Pan et al., 2021)
3. miR-1248 SINE/Alu t (Lin et al., 2023)
4. miR-1253 LINE2 h SINE/MIR i (Wang et al., 2020)
5. miR-1257 ERVL t (Xu, Li, 2016)
6. miR-1264 LINE2 i (Wen et al., 2021)
7. miR-1271 LINE2 t (Long et al., 2021)
8. miR-1273 LINE, SINE, ERVL t (Wang et al., 2015)
9. miR-1278 SINE/MIR i (Ma et al., 2023)
10. miR-1296 LINE2 i (Niu et al., 2021)
11. miR-151 LINE2 i (Chen et al., 2021)
12. miR-192 LINE2 t (Zhao et al., 2021)
13. miR-211 LINE2 i (Zhang et al., 2021)
14. miR-28 LINE2 t (Liu et al., 2015a)
15. miR-2909 LTR-ERVL t (Arora et al., 2014)
16. miR-31 LINE2 t (Liu et al., 2015b)
17. miR-320b LINE2 t (Lu et al., 2022)
18. miR-326 LINE2 t (Wang et al., 2019).
19. miR-335 SINE/MIR t (Hildebrandt et al., 2021)
20. miR-342 SINE/tRNA-RTE t (Ahmadi et al., 2018)
21. miR-3646 SINE/MIR t (Fan et al., 2020)
22. miR-374 LINE2 t (Wang W. et al., 2020)
23. miR-378 SINE/MIR, LINE2 t (Shao et al., 2018)
24. miR-384 LINE-Dong-R4 t (Wang et al., 2016)
25. miR-421 LINE2 i (Yang et al., 2020)
26. miR-4286 ERVL i (He et al., 2020)
27. miR-4459 SINE/Alu i (Lin et al., 2022)
28. miR-4487 LINE1 t (Liang et al., 2022)
29. miR-4731 LINE-CR1 t (Ye et al., 2020)
30. miR-487 SINE/MIR t (Wang et al., 2021)
31. miR-493 LINE2 i (Niu et al., 2021)
32. miR-495 ERVL i (Rafiq et al., 2023)
33. miR-498 LINE1 t (Liu et al., 2020)
34. miR-502 LINE2 t (Wang et al., 2014)
35. miR-511 LINE1 t (Karagiannis et al., 2013)
36. miR-520d SINE/Alu i (Salerno et al., 2020).
37. miR-544 LINE1 i (Guo et al., 2020)
38. miR-548 LINE, HERV, SINE i (Konwerski et al., 2021)
39. miR-552 LINE1 t (Feng et al., 2022)
40. miR-576 LINE1 i (Zhang et al., 2022)
41. miR-579 LINE1 i (Wang et al., 2024)
42. miR-582 LINE-CR1 t (Hildebrandt et al., 2021)
43. miR-612 SINE/MIR i (Chen et al., 2018)
44. miR-616 LINE2 t (Chen et al., 2020)
45. miR-630 SINE/MIR i (Miao et al., 2022)
46. miR-633 SINE/MIR i (Hou et al., 2022)
47. miR-637 LINE1 i (Zhang et al., 2023)
48. miR-641 SINE/MIR i (Ma et al., 2021)
49. miR-664a LINE1 i (Li et al., 2018)
50. miR-708 LINE2 i (Chen et al., 2015)
51. miR-769 LINE/CR1 t (Hildebrandt et al., 2021)
52. miR-7975 LTR-ERV1 t (Karere et al., 2023).
53. miR-942 LINE2 i (Yang et al., 2023)
(Ye et al., 2020), miR-552 (HHrHÔupyer SKI u ATF4 (Fang et al., 2022)), miR-579 (Wang et al., 2024), miR-612 (Chen et al., 2018), miR-630 (Miao et al., 2022), miR-641 (Ma et al., 2021). MiR-511 is a component of a multisubunit complex involved in the terminal stages of cholesterol synthesis with the regulation of a family of GPCR proteins that are involved in the transformation of VSMC phenotypes and the pathogenesis of AS (Karagiannis et al., 2013).
A number of microRNAs derived from retroelements affect the expression of EC genes and their precursors, for example, miR-1248 suppresses the expression of thrombomodulin (Lin et al., 2023), microRNA miR-151 (targeting IL-17A, c-caspases 3 and 9, BAX) inhibits EC apoptosis (Chen et al., 2021). In AS, a low level of miR-4286 was detected, which inhibits TGF-ß1 (promotes damage to the ECs (He et al., 2020)). MiR-487 inhibits p53 and CBP, enhancing EC proliferation (Wang et al., 2021). MiR-544 promotes the maturation and antioxidant properties of EC-like cells by regulating the YY1/TET2 signaling pathways (Guo et al., 2020). MiR-637 suppresses TRAF6 expression, promoting EC proliferation and angiogenesis, inhibiting apoptosis and inflammation (Zhang et al., 2023). MiR-708 is expressed in EC in AS and inhibits the expression of IL-1 receptor-associated kinase, IL-6 receptor, conserved helix-loop-helix ubiquitous kinase, nuclear factor kB kinase subunit-y inhibitor (Chen et al., 2015). High levels of miR-769, which targets GSK3B and TRAPPC2B (Hildebrandt et al., 2021) and miR-7975, proposed as a potential biomarker of AS, were detected in the arteries of patients with AS (Karere et al., 2023).
MicroRNAs derived from REs influence AS by regulating immune processes. Thus, miR-1257, involved in the MHC protein assembly pathways, inhibits CALR, POMC, TLR4, IL10, ATF6, promoting the progression of CAD (Xu, Li, 2016). MiR-28 increases ABCA1 expression, which correlates with LXRa translation activation in macrophages (Liu et al., 2015a). MiR-2909 regulates genes involved in inflammation and immunity (Arora et al., 2014).
RE-derived microRNAs also influence AS by modulating epigenetic factors. Thus, miR-
1264 suppresses the expression of DNMT1 and phosphorylated STAT3 (Wen et al., 2021). MiR-630 targets the methyltransferase EZH2, which modulates TIMP2 transcription in regulating VSMC migration and promoting AS (Miao et al., 2022).
MicroRNAs are involved in the pathogenesis of AS through their effects on macrophages. Thus, miR-320b (Lu et al., 2022) and miR-378 (Shao et al., 2018) regulate cholesterol efflux from macrophages. Administration of miR-320b to animals increased the size of AS plaques, the content of damaged macrophages and cytokine levels due to increased phosphorylation of NF-kB (Lu et al., 2022). MiR-326 is involved in the formation of oxidized foam cells in AS (Wang et al., 2019). MiR-384 accelerates the development of AS by disrupting macrophage autophagy (Wang et al., 2016).
A number of microRNAs derived from RE and involved in the pathogenesis of AS interact with lncRNAs in these processes. These include miR-326 (Wang et al., 2019), miR-4731 (interacts with lncRNA SENCR (Ye et al., 2020)). NORAD silencing increases miR-495 levels, inhibiting AS plaques by reducing KLF5 expression (Fu et al., 2021). In the serum of patients with AS, the levels of PON1 and lncRNA, which acts as a competitive endogenous RNA for miR-616, are reduced (inhibits PON1 expression, promotes AS (Chen et al., 2020)). LncRNA MIAT interacts with miR-641, affecting the proliferation and migration of VSMCs (Ma et al., 2021). LncRNA Punisher regulates apoptosis and mitochondrial homeostasis of VSMCs by interacting with miR-664a (Yang et al., 2022b).
MicroRNAs arising from REs are also involved in the pathogenesis of AS through interaction with circular RNAs: miR-495 binds to hsa_circ_0126672 (Rafiq et al., 2023). Circ_0086296 induces AS through the IFIT1/STAT1 feedback loop, acting as a sponge for miR-576, which inhibits the expression of IFIT1-STAT1, preventing the development of AS (Zhang et al., 2022a). Hsa_circ_0031891 targets miR-579 to enhance HMGB1 expression (Wang et al., 2024). Cir-cARHGAP12, which stimulates VSMC proliferation and migration, binds to miR-630 (Miao
et al., 2022). Hsa_circ_0008896 has a similar mechanism of action, affecting VSMCs through interaction with miR-633 and regulating CDC20B (Hou et al., 2022). Circ_0003575 interacts with miR-637 and also activates the NF-kB pathway (Zhang et al., 2023). MiR-942, targeting the GPR56 adhesin family gene (Caparosa et al., 2019), interacts with circ_0090231 to inhibit VSMC proliferation and migration (Yang et al., 2023).
RE-derived microRNAs are also involved in cholesterol metabolism in the pathogenesis of AS. Thus, miR-498 inhibits the SCD (stearoyl-CoA desaturase) gene, which reduces serum cholesterol levels (Liu et al., 2020). MiR-520d inhibits the expression of PCSK9, which causes degradation of low-density lipoprotein receptors, suppressing the development of AS (Salerno et al., 2020).
Conclusion
In the pathogenesis of AS, an important role is played by aging-induced hyperactiva-tion of retroelements, which leads to IFN
stimulation, various immunopathological processes and changes in the phenotype of VSMCs, ECs and macrophages due to the influence of microRNAs derived from REs on gene expression. Various viral infections are also important, under the influence of which REs is activated as a protective reaction of cells, which can lead to the early onset and rapid progression of AS. Since ERs are sources of lncRNAs and microRNAs, impaired expression of non-coding RNAs in AS reflects dysregulation of REs. This is evidenced by an analysis of the MDTE DB database, in which 53 microRNAs derived from REs were found, the expression of which changes in AS. In accordance with this, targeted therapy using specific microRNAs aimed at pathologically activated REs involved in the pathogenesis of AS may become a promising method for treating the disease.
The author declares no conflicts of interest.
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