Next Article in Journal
Editorial for the Special Issue “Advanced Research in Plant Metabolomics”
Previous Article in Journal
Increase in Double Negative B Lymphocytes in Patients with Systemic Lupus Erythematosus in Remission and Their Correlation with Early Differentiated T Lymphocyte Subpopulations
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
CIMB
Volume 45
Issue 8
10.3390/cimb45080422
cimb-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Circular RNAs Variously Participate in Coronary Atherogenesis

by
Liudmila V. Dergunova
1,*,
Margarita A. Vinogradina
1,
Ivan B. Filippenkov
1,
Svetlana A. Limborska
1 and
Alexander D. Dergunov
2
1
Laboratory of Human Molecular Genetics, National Research Center “Kurchatov Institute”, Kurchatov Sq. 2, Moscow 123182, Russia
2
Laboratory of Structural Fundamentals of Lipoprotein Metabolism, National Medical Research Center for Therapy and Preventive Medicine, Petroverigsky Street 10, Moscow 101990, Russia
*
Author to whom correspondence should be addressed.
Curr. Issues Mol. Biol. 2023, 45(8), 6682-6700; https://doi.org/10.3390/cimb45080422
Submission received: 29 June 2023 / Revised: 3 August 2023 / Accepted: 11 August 2023 / Published: 13 August 2023
(This article belongs to the Topic Blood Physiology: Molecular Mechanisms of Vascular Wall Functioning, 2nd Volume)
Browse Figures
Versions Notes

Abstract

:
Over the past decade, numerous studies have shown that circular RNAs (circRNAs) play a significant role in coronary artery atherogenesis and other cardiovascular diseases. They belong to the class of non-coding RNAs and arise as a result of non-canonical splicing of premature RNA, which results in the formation of closed single-stranded circRNA molecules that lack 5′-end caps and 3′-end poly(A) tails. circRNAs have broad post-transcriptional regulatory activity. Acting as a sponge for miRNAs, circRNAs compete with mRNAs for binding to miRNAs, acting as competing endogenous RNAs. Numerous circRNAs are involved in the circRNA–miRNA–mRNA regulatory axes associated with the pathogenesis of cardiomyopathy, chronic heart failure, hypertension, atherosclerosis, and coronary artery disease. Recent studies have shown that сirc_0001445, circ_0000345, circ_0093887, сircSmoc1-2, and circ_0003423 are involved in the pathogenesis of coronary artery disease (CAD) with an atheroprotective effect, while circ_0002984, circ_0029589, circ_0124644, circ_0091822, and circ_0050486 possess a proatherogenic effect. With their high resistance to endonucleases, circRNAs are promising diagnostic biomarkers and therapeutic targets. This review aims to provide updated information on the involvement of atherogenesis-related circRNAs in the pathogenesis of CAD. We also discuss the main modern approaches to detecting and studying circRNA–miRNA–mRNA interactions, as well as the prospects for using circRNAs as biomarkers and therapeutic targets for the treatment of cardiovascular diseases.

1. Introduction

Coronary artery disease (CAD), caused by atherosclerotic processes, continues to be the leading cause of morbidity and mortality in the adult population in developed countries. This disease occurs as a result of chronic inflammation of the subendothelial layer of the arteries, the accumulation of lipids and fibrous elements in their walls, the formation of coronary plaques, and the narrowing of the lumen of the vessels. Atherosclerotic damage to the vascular wall is associated with disruption of the functioning of multiple genes, epigenetic modifications, and exposure to environmental factors [1,2,3].
Transcriptomic studies indicate that a large part of the human genome is transcribed into non-coding RNAs (ncRNAs), which play a significant role in the pathogenesis of cardiovascular disease (CVD) [4]. ncRNAs are involved in the regulation of transcription [5,6], splicing, translation, and post-transcriptional regulation of gene expression [7]. Based on length and structure, ncRNAs are classified into three main categories: microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs). miRNAs are 18–25 nucleotides long. They can bind to a recognition element in the 3′-untranslated region (3′-UTR) of mRNA, disrupting mRNA or inhibiting its translation and thus negatively controlling gene expression. It is believed that miRNAs can regulate more than half of the genes encoding human proteins [8]. By inhibiting the expression of genes involved in reverse cholesterol transport in macrophages, miRNAs play a key role in the regulation of lipid disorders and atherogenesis [9,10,11,12,13,14]. Since complementarity of 6–8 bases is sufficient to form a miRNA/mRNA duplex, a single miRNA molecule can target a wide range of different mRNAs, while a single mRNA can be attacked by several miRNAs. This creates a complex regulatory RNA–RNA network [15,16].
lncRNAs with a length of more than 200 nucleotides play an essential role in the regulation of transcription and in the post-transcriptional regulation of the expression of genes involved in the pathogenesis of atherosclerosis [9,17,18,19]. Depending on the specific interaction with DNA, RNA or proteins, lncRNAs can participate in promoter activation during transcription initiation and splicing, and change the stability and translation of cytoplasmic mRNAs [20]. lncRNAs can compete with mRNA for miRNA binding. At the same time, they reduce the effect of miRNA, which suppresses the expression of target genes. Thus, lncRNAs promote an increase in the expression of these genes [21]. These lncRNAs are considered as competing endogenous RNAs (ceRNAs).
Over the past decade, numerous studies have shown that circRNAs play a significant role in the pathogenesis of CAD and other CVDs [11,22,23,24]. circRNAs arise as a result of non-canonical premature RNA (pre-mRNA) splicing, in which closed circular molecules are formed [25]. circRNAs have broad post-transcriptional regulatory activity, acting as ceRNAs [21,26]. Acting as sponges for miRNAs [27,28], they are involved in the circRNA-miRNA–mRNA regulatory axes associated with the pathogenesis of cardiomyopathy, chronic heart failure, hypertension, atherosclerosis, and CAD [29,30,31]. With their high resistance to endonucleases, circRNAs are promising diagnostic biomarkers and therapeutic targets. Circular RNAs, underestimated for a long time, are receiving great attention now, evidenced by a noticeable growth in publications on their role in the pathogenesis of various diseases. Here we review the recent data on the involvement of circRNAs in coronary atherogenesis and highlight the main modern approaches to detecting and studying circRNA–miRNA–mRNA interactions and the major efforts in the study of mechanisms and the end-effects of circRNAs’ action on CAD. The directions of future research of circRNAs, the perspectives for their application, and possible drawbacks in CAD therapy are discussed as well.

2. Characteristics and Functions of circRNAs

RNA molecules that form a continuous structure were first described by Diener in 1971 when studying infectious single-stranded covalently closed RNA molecules that cause spindle tuber disease of potato (PST viroid) [32]. The term “circular RNA” (circRNA) was proposed in 1976 by Sanger et al. when they characterized the structure of viroids [33]. In 1979, the presence of circRNA in the cytoplasm of eukaryotic cells was demonstrated [34]. The detected circRNAs were considered non-functional or splicing by-products; however, with the development of high-throughput sequencing and bioinformatics approaches, it was found that circRNAs are highly expressed in all eukaryotic cells and perform certain functions [35]. Recent studies have shown that circRNAs are critical regulators of cell physiology and various pathologies by modulating gene expression [29,36,37,38,39].
Most circRNAs are formed by backsplicing exons or introns of pre-mRNA genes encoding proteins. As a result, the downstream 5′ splicing site is connected to the upstream 3′ splicing site. Thus, a circular RNA molecule with a 3′–5′-phosphodiester bond is formed [40]. The absence of terminal structures increases their stability compared to linear transcripts [35]. circRNAs can be formed from exons (ecircRNAs), introns (ciRNAs), or exon-intron sequences (elciRNAs) [35,41]. ciRNAs and elciRNAs are located in the nucleus, and their main function is cis-regulation of parental gene expression [40,42,43]. Most of the known circRNAs are ecircRNAs. They are found predominantly in the cytoplasm. The functions of circRNA include regulation of transcription mediated by polymerase II (Pol II) [40], regulation of post-transcriptional gene expression as a sponge for miRNA or protein [5,28,44,45], interaction with RNA-binding proteins (RBP), the ability to regulate their availability in the cell, modulation of protein–protein interactions [46,47] and acting as a matrix for protein translation [48]. In addition to serving as miRNA sponges, circRNAs are also associated with the storage and localization of miRNAs [49].

3. Biogenesis and Degradation of circRNAs

Biogenesis and degradation of circRNA have been described in sufficient detail [25,50,51,52,53]. The pathways for circRNA formation and degradation are summarized in Figure 1. Spliceosomal machinery is regarded as a primary procedure of circRNA formation. There are three types of biogenesis model, including circularization driven by intron pairing (inverted repeat pairing) [54,55,56], circularization driven by RNA-binding protein (RBP) Muscleblind (MBL) [57], Quaking (QKI) [58], FUS [59], RBM3 [60], and others, as well as lariat-triggered circularization [35,61]. Lariats contain a significant intronic sequence and involve a 2′–5′ phosphodiester linkage at a branch point. In lariat-driven circularization, intronic lariats can be processed into circular intronic RNA (ciRNA) during splicing. The latter model is more characteristic of ciRNAs. There are also known factors that affect the accumulation of circRNAs in the cell. Among them are the restrictions on splicing and polyadelinylation factors [62], reduced activity of the ADAR1 (which reduces pairing of lateral introns) [63], and DHX9 (which unravels paired introns) enzymes [64], and the inhibition of poly (ADP-ribose) polymerase 1 (PARP1) activity [65]. Furthermore, this regulation of PARP1 within host genes acts to fine tune their transcriptional output, with implications in gene function.
Due to the stability of circRNAs compared to linear RNAs, circRNAs are capable of accumulating in cells. However, ways to reduce their numbers are also known [53]. They include RNase H-dependent cleavage of circRNAs in the nucleus when circRNAs interact with single-strand DNA during the formation of R-loops [66]. The pathways of circRNA cleavage in the cytoplasm are also shown. One of them is related to the activity of RNase L, which functions at the stage of the primary immune response to cleave viral and some cellular RNAs [67,68]. circRNAs tend to form RNA duplexes of 16–26 bp and act as endogenous inhibitors of double-stranded RNA-dependent protein kinase (PKR). Thus, it has been suggested that RNase L-mediated circRNA degradation is required for PKR activation during viral infection [68]. Another circRNA degradation pathway involves the cleavage of m6A-containing RNAs via the YTHDF2–HRSP12–RNase–P/MRP pathway [69]. Structure-mediated RNA decay (SRD) has also been described under the influence of endoribonucleases, the signal for which is the binding of UPF1 and G3BP1 proteins to highly structured circRNA motifs [70]. In the pioneering study by Hansen et al., the circRNA degradation pathway was described in an AGO-dependent manner when Ago2 cleaved circRNA after recognizing the microRNA complex [71]. It was noted that the mechanism implemented in the nucleus is apparently not common [72,73]. The separate pathway for the removal of circRNA from cells due to packaging and transportation in exosomes has been described [74,75]. The exosomes are membrane-bound extracellular vesicles (EVs) that are produced in the endosomal compartment of most eukaryotic cells [76]. EVs are nano-sized (30–150 nm) biovesicles containing DNA, RNA, and proteins. EVs are released into the surrounding extracellular fluid upon fusion between multivesicular bodies and the plasma membrane [77]. The level of circRNAs in a cell is determined by the ratio of biogenesis and degradation rates.

4. Main Approaches for Studying the Role of circRNA in the Pathogenesis of CAD

High-throughput RNA sequencing (RNA-Seq) has made it possible to identify thousands of circRNAs involved in physiological processes and in the pathogenesis of various diseases [78,79,80,81,82]. The most commonly used way to detect differentially expressed circRNAs (DECs) includes a comparative analysis of their representation in experimental and control biological samples using microarrays or RNA-Seq. Sanger sequencing (Sanger-Seq) and exonuclease R processing are used to confirm the cyclic structure of the molecule. The expression level of DECs in biological samples is determined using the reverse transcription polymerase chain reaction (RT-PCR) method. Bioinformatics analysis is being applied to elucidate the specific mechanisms by which circRNAs are involved in disease development. First, the search for microRNA targets of circRNAs is carried out. The selected miRNAs are then searched for mRNAs to which they can bind. The next step for the correct validation of circRNA–miRNA–mRNA interactions is their experimental validation in pathological conditions or in cell culture models of atherosclerosis in vitro. Dual-luciferase reporter (DLR) analysis, RNA pull-down (RPD) assays, and RNA immunoprecipitation (RIP) are used as experimental tools. Cultures of human aortic endothelial cells (HAEC), human umbilical vein endothelial cells (HUVEC), or human aortic smooth muscle cells (HASMC) treated with oxidized low-density lipoproteins (OX-LDL) are predominantly used to simulate atherosclerotic conditions [83]. Ox-LDLs induce an inflammatory response; proliferate, migrate towards, and invade smooth muscle cells (HASMCs); block endothelial cell proliferation; and induce cell apoptosis [84,85,86]. The scheme of methods and approaches used to identify the role of circRNAs in the pathogenesis of CAD is presented in Figure 2.

5. The Role of circRNAs in the Pathogenesis of CAD and Atherogenesis

The nature of cellular and molecular events in atherogenesis associated with CAD is described in detail [87,88,89]. Atherosclerosis is considered a chronic inflammatory disease caused by the accumulation of lipids in the intima of the arteries and the development of inflammatory reactions. The inflammatory process in atherogenesis is mediated by chemokines, cytokines, adhesion molecules, and other factors produced by various cells, including macrophages, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs) [90,91]. EC dysfunction, transformation, abnormal proliferation and migration of VSMCs; formation of foam cells; and recruitment of macrophages, T-lymphocytes, and platelets contribute to the progression of atherosclerosis [92]. In recent years, a large number of studies have identified circRNAs involved in the regulation of gene expression associated with CAD [4,93,94]. Microarray analysis of DECs in the plasma of three CAD patients found that, compared to controls, 18 circRNAs were upregulated and six were downregulated [95]. Using miRanda software, the authors showed that nine circRNAs among them could potentially bind to hsa-miR-130a-3p. The mRNA of transient receptor potential cation channel subfamily M member 3 (TRPM3) was identified as a target for hsa-miR-130a-3p. Based on these data, a circRNA–miRNA–mRNA network with nine circRNAs and one mRNA was constructed for hsa-miR-130a-3p. Upon inhibition of hsa-miR-130a-3p, the identified circRNAs promoted the expression of the TRPM3 gene. In another study, genome-wide transcriptome analysis of circRNAs revealed 13,160 downregulated and 12,905 upregulated circRNAs in peripheral blood mononuclear cells from five CAD patients and five controls [78]. Possible target miRNAs were identified for 10 circRNAs using miRanda and TargetScan software; their mRNA targets were identified; and circRNA–miRNA–mRNA networks were constructed using Cytoscape. Whole-transcriptome profiling of circRNA expression in segments of the coronary arteries of patients with CAD was performed. circRNAs have been identified that may play an important role in the progression of human coronary atherosclerosis and may serve as a diagnostic or therapeutic target against CAD. It should be noted that the mechanism of circRNAs’ action in studied conditions remains unknown [96,97].
A notable contribution to the study of the molecular mechanism of action of circRNAs in atherosclerosis was made by experiments confirming the axes of circRNAs, miRNAs, and mRNAs in the serum of CAD patients or in cultures of HAEC, HUVEC, or VSMC cells treated with ox-LDL as models of atherosclerosis in vitro. Quantitative analysis revealed both a decrease and an increase in the levels of different circRNAs in the studied biological samples. Table 1 lists circRNAs that are downregulated in the serum of patients with atherosclerosis or in cell cultures simulating atherosclerosis. The circRNA–miRNA–mRNA axes, the methods used to validate them, the effect, and the potential applications of circRNAs are also included for each circRNA.
Downregulated circRNAs in the plasma of patients suffering from atherosclerosis have an anti-inflammatory effect, reduce oxidative stress, and reduce vascular calcification (Table 1). The atheroprotective effect of the presented circRNAs is manifested by an increase in proliferation and a decrease in apoptosis on cultures of HAEC and HUVEC endothelial cells treated with ox-LDL, while a decrease in proliferation is noted on VSMC.
It should be noted that, being sponges for different miRNAs, individual circRNAs are involved in several circRNA–miRNA–mRNA interactions. So, for circ_0000345, three axes of circRNA–miRNA–mRNA were experimentally confirmed (Table 1) [84,104,105]. The reduced content of circ_0000345 in the serum of patients with atherosclerosis and in ASMC, HAEC, and HUVEC cell cultures treated with ox-LDL was accompanied by an increase in the content of various miRNAs. At the same time, circ_0000345 acts as a sponge for miR-647 miRNA and increases PAPD5 expression with a concomitant reduction in inflammatory response, proliferation, and ASMC migration [84]. circ_0000345 was found to be able to protect in vitro HAEC cell culture from ox-LDL-induced damage via the miR-758/CCND2 axis, promoting cell viability and cell proliferation, and inhibiting cell apoptosis [104,105]. A decrease in the level of miR-129-5p was found in experiments on the overexpression of circ_0000345 in HUVEC cells. The results confirmed the competitive endogenous role of circRNA. At the same time, the level of circ_0000345 correlated with an increase in the level of Tet methylcytosine dioxygenase 2 (TET2) mRNA [105].
The protective effect of circ_0001445 is shown, the level of which is also markedly reduced in the serum of patients with CAD [114]. Cai et al. found that overexpression of hsa_circ_0001445 in ox-LDL-induced HAEC promoted cell proliferation, inhibited cell apoptosis, suppressed the inflammatory response, and suppressed the expression of TNF-α, IL-1β and IL-16 [115]. It was shown that miRNA-640 was a direct target for hsa_circ_0001445. The authors concluded that hsa_circ_0001445 had an atheroprotective effect via miRNA-640. According to Yang et al., circ_0001445 possesses binding sites for miR-208b-5p, which in turn targets ABCG1 mRNA [110]. Binding of miR-208b-5p with circ_0001445 or ABCG1 has been confirmed using a DLR, RIP, and RPD (Table 1) [115]. Being a sponge for miR-208b-5p, circ_0001445 has an atheroprotective effect by inhibiting ox-LDL-induced HUVEC inflammation, oxidative stress, apoptosis, and foam cell formation. New circRNA–miRNA–mRNA regulatory networks have recently been constructed for hsa_circ_0001445 [116]. Bioinformatics analysis revealed an association of hsa_circ_0001445 with three miRNAs (hsa-miR-507, hsa-miR-375-3p, and hsa-miR-942-5p). The interaction network of miRNAs with 18 genes in the KEGG pathway was established; however, these results have yet to be confirmed experimentally. Thus, atherogenesis-related circRNAs, whose expression level is reduced in the plasma of patients with atherosclerosis, have an atheroprotective effect under conditions of experimental atherosclerosis in vitro and can potentially be used for CAD therapy.
Table 2 lists circRNAs that are upregulated in the serum of patients with atherosclerosis or in cell culture models of atherosclerosis. The circRNA–miRNA–mRNA axes, the methods used to validate them, the effect, and the potential applications of circRNAs are also included for each circRNA.
In the vast majority of cases, an increase in the content of circRNA is accompanied by activation of inflammation, oxidative stress, abnormal proliferation and migration of VSMC, and suppression of HUVEC proliferation. An increase in the level of circRNA can lead to an increase in the expression of ICAM-1 and VCAM-1 [135], lipid metabolism disturbances, the formation of foam cells [147,148], and other manifestations of atherosclerosis. Thus, atherogenesis-related circRNAs, whose expression level is increased with an overall proatherogenic effect, can be biomarkers and targets for CAD therapy.
One of the main risk factors for the development of atherosclerosis in humans is the increased level of cholesterol in the serum [153]. Quite recently, more than a hundred circRNA–miRNA–mRNA interactions involved in atherogenesis during foam cell formation have been described [160]. It was shown that 88 circRNAs, acting as sponges for 33 miRNAs, affect the expression of SR-A1, CD36, ACAT2, ABCA1, ABCG1, ADAM10, APOA1, SCARB1. The protein products of these genes are involved in cholesterol uptake, esterification, and efflux [161]. Thus, circRNAs are involved in coronary artery atherogenesis by various mechanisms with different circRNA–miRNA–mRNA interactions leading, in turn, to atheroprotective or proatherogenic effects in CAD.

6. CircRNAs Are Promising Biomarkers and Therapeutic Targets for the Treatment of CAD

The increased stability of circRNAs compared to linear transcripts, their specificity, reproducibility, and difference in expression levels in normal and pathological conditions have led to their identification as a diagnostic and prognostic marker of many diseases, including CAD [81,160,162,163]. circRNAs can be isolated from biomaterials such as cerebrospinal fluid, saliva, serum, plasma, and urine, as well as from circulating cells and exosomes [164]. The results of circRNA measurement with RT-PCR or RNA-Seq can be used for early diagnosis, treatment selection, disease prognosis, and treatment control [163]. The circRNA level can serve as a potential biomarker of CAD in different samples, such as: peripheral blood (has_circ_0124644) [165]; mononuclear cells (BTBD7_hsa_circ_0000563, hsa_circ_0001879, and has_circ_0004104) [47,166]; plasma and peripheral blood leukocytes (hsa_circ_0001445) [114,116]; and extracellular vesicles (hsa_circ_0005540) [167]. As can be seen from Table 1 and Table 2, dozens of circRNAs are currently considered risk factors for the development of CAD, making them potential biomarkers and possible targets for the treatment of this pathology. To date, there is no unequivocal answer as to whether circRNAs in blood cells or in other biomaterials reflect pathological processes occurring in atherosclerosis and, in particular, in CAD. It is still a controversial question whether signatures of gene expression in the blood can serve as biomarkers of disease states [168]. In a comparison of 15 studies in which 706 differentially expressed genes were identified, only 23 genes were replicated in no more than two or three studies. The low level of replication, according to the authors, is due to genetic differences in how an individual responds to a disease. Studies with cohorts of more than 5000 people looking at the impact of common genetic variants still failed to state that disease-specific genes may belong to biomarkers. Based on the results of the study, it was concluded that in order to overcome the heterogeneity of the response to the disease, it is necessary to use significantly larger samples of the studied case-control cohorts. At the same time, it has been shown that miRNAs are less affected by genetic differences and can more accurately reflect the disease process [168]. Thus, the question of how genetic differences can affect the content of circRNAs and whether they can be biomarkers remains open. In addition, it should be taken into account that one circRNA can adsorb several miRNAs, one miRNA molecule can target a wide range of different mRNAs, and individual circRNAs can be markers of several diseases simultaneously. An interesting idea is to use the ratios of circRNA and miRNA levels as biomarkers; for example, the circR-284/miR-221 ratio has been proposed as a marker for predicting carotid artery disease and stroke [169].
The use of circRNAs as therapeutic targets in CAD has been widely discussed [24,29,170]. An attractive therapy strategy is the creation and use of artificial circRNAs in the form of miRNA sponges [171]. The advantages and disadvantages of the methodology of circRNA synthesis in vitro have been thoroughly reviewed recently [170]. The use of newly synthesized circRNAs is restricted by imperfect cyclization, the presence of extraneous fragments, their off-target effects, and the activation of the immune response. The future improvement of circRNA synthesis technologies is required to receive safe preparations. However, RNA delivery to cells and organs is a serious problem that needs to be solved for clinical applications. Most often, viral systems are used for RNA delivery. Due to its low immunogenicity, adeno-associated virus (AAV) is one of the most promising delivery systems in translational medicine. Since AAVs do not integrate DNA into the genome of host cells, this avoids unwanted off-target changes in gene expression. Currently, most animal studies studying the cardiovascular system are focused on the application of circRNA through AAV delivery systems. A limitation of the use of AAV is the presence of a large population of neutralizing antibodies against it [170].
New horizons in modern CAD therapy for successful drug delivery were opened by EVs (exosomes) [172]. Such key qualities of EVs as low immunogenicity, high physicochemical stability, the ability to penetrate tissues, and the innate ability to bind to other cells ensured their therapeutic application [173]. Recently, the therapeutic potential of exosomes derived from circRNA_0002113 lacking mesenchymal stem cells in myocardial infarction has been shown. So, the circRNA_0002113/miR-188-3p/RUNX1 axis-mediated alleviation of apoptosis serves as a novel strategy to treat myocardial ischemia/reperfusion injury [174]. circRNAs in exosomes are being tested as potential CAD treatments, but it should be noted that the use of circRNAs in exosomes is also limited by the lack of data on the functioning of the exosomes themselves (low efficiency and safety of the proposed technologies).
Besides the difficulties in circRNA’s development and the systems of safe delivery, the existence of several points of application, several mechanisms of action, and their involvement in the progression of multiple human diseases are major drawbacks in circRNA’s use for diagnostics and therapy. Indeed, one circRNA can adsorb several miRNAs, one miRNA molecule can target a wide range of different mRNAs with the involvement of corresponding protein products in the development of several pathologies, and individual circRNAs can be markers of several diseases simultaneously. Many circRNAs, in particular circMTO1, circHIPK3, сirc_0001946, circPTPRA, and circCOL1A1, are potential targets for therapy or biomarkers of CAD (Table 1 and Table 2), and play critical roles in cancer progression as well [175,176,177,178,179]. Additional comprehensive studies of the action mechanisms of individual circRNAs and the involved regulatory networks are needed.

7. Conclusions

The latest achievements of the numerous studies of the expression and action mechanisms of tens of atherogenesis-related circRNAs associated with CAD are discussed here. circRNAs, as microRNA sponges, can be risk factors, potential biomarkers, and therapeutic agents for coronary artery disease. Atherogenesis-related circRNAs with decreased plasma levels in patients with atherosclerosis or in vitro conditions as a model of atherosclerosis possess anti-inflammatory and atheroprotective effects, decrease oxidative stress, and may be used potentially for CAD treatment. Other circRNAs with increased expression possess a proatherogenic effect and may serve as diagnostic and therapeutic targets. Thus, the studies of circRNAs involved in atherosclerosis of coronary arteries and their participation in various circRNA–miRNA–mRNA regulatory axes contribute both to understanding CAD development and their potential use for diagnostics and therapy.

8. Future Directions

The practical use of circRNAs at present is largely restricted. A majority of studies evidence the role of circRNAs as microRNA sponges; however, the full set of circRNA functions remains to be answered. Recent studies have established that circRNAs regulate gene expression by associating with RNA-binding proteins [46,47,180]. Accumulating studies indicate that circRNA encode proteins or peptides [181,182,183,184,185] that challenges the general opinion on their non-coding properties. Future studies of circular RNAs may be directed toward their regulatory and translational potential and their biogenesis and degradation. Due to the involvement of a large number of circular RNAs in various physiological and pathological processes and in the pathogenesis of various diseases, the full spectrum of circRNAs circulating in the bloodstream of CAD patients, the underlying network characteristics, and the use of large cohorts are the primary requests for the selection of promissory circRNAs as biomarkers or therapeutic agents. The relationship between circRNA activity and the genomic architecture of individuals and populations has to be considered in personalizing health care. We believe the successful treatment of cardiovascular diseases by circRNA is based upon the new circRNA–miRNA–mRNA regulatory axes and fundamental principles of circRNA biology.

Author Contributions

Conceptualization, L.V.D. and A.D.D.; methodology, L.V.D. and I.B.F.; software, M.A.V. and I.B.F.; validation, L.V.D., I.B.F. and A.D.D.; formal analysis, L.V.D., M.A.V. and I.B.F.; investigation, L.V.D., M.A.V. and I.B.F.; resources, L.V.D.; data curation, L.V.D., I.B.F. and A.D.D.; writing—original draft preparation, L.V.D., M.A.V. and I.B.F.; writing—review and editing, L.V.D., I.B.F., S.A.L. and A.D.D.; visualization, L.V.D., M.A.V. and I.B.F.; supervision, L.V.D., S.A.L. and A.D.D.; project administration, S.A.L. and A.D.D. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Thematic plan of the National Research Center “Kurchatov Institute”.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Takahashi, K.; Takeya, M.; Sakashita, N. Multifunctional Roles of Macrophages in the Development and Progression of Atherosclerosis in Humans and Experimental Animals. Med. Electron. Microsc. 2002, 35, 179–203. [Google Scholar] [CrossRef]
  2. Rudijanto, A. The Role of Vascular Smooth Muscle Cells on the Pathogenesis of Atherosclerosis. Acta Med. Indones. 2007, 39, 86–93. [Google Scholar]
  3. Baumer, Y.; McCurdy, S.; Alcala, M.; Mehta, N.; Lee, B.-H.; Ginsberg, M.H.; Boisvert, W.A. CD98 Regulates Vascular Smooth Muscle Cell Proliferation in Atherosclerosis. Atherosclerosis 2017, 256, 105–114. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Ghafouri-Fard, S.; Gholipour, M.; Taheri, M. The Emerging Role of Long Non-Coding RNAs and Circular RNAs in Coronary Artery Disease. Front. Cardiovasc. Med. 2021, 8, 632393. [Google Scholar] [CrossRef]
  5. Guttman, M.; Amit, I.; Garber, M.; French, C.; Lin, M.F.; Feldser, D.; Huarte, M.; Zuk, O.; Carey, B.W.; Cassady, J.P.; et al. Chromatin Signature Reveals over a Thousand Highly Conserved Large Non-Coding RNAs in Mammals. Nature 2009, 458, 223–227. [Google Scholar] [CrossRef] [PubMed]
  6. Khalil, A.M.; Guttman, M.; Huarte, M.; Garber, M.; Raj, A.; Rivea Morales, D.; Thomas, K.; Presser, A.; Bernstein, B.E.; van Oudenaarden, A.; et al. Many Human Large Intergenic Noncoding RNAs Associate with Chromatin-Modifying Complexes and Affect Gene Expression. Proc. Natl. Acad. Sci. USA 2009, 106, 11667–11672. [Google Scholar] [CrossRef] [PubMed]
  7. Okamura, K.; Lai, E.C. Endogenous Small Interfering RNAs in Animals. Nat. Rev. Mol. Cell Biol. 2008, 9, 673–678. [Google Scholar] [CrossRef] [Green Version]
  8. Friedman, R.C.; Farh, K.K.H.; Burge, C.B.; Bartel, D.P. Most Mammalian MRNAs Are Conserved Targets of MicroRNAs. Genome Res. 2009, 19, 92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Rozhkova, A.V.; Dmitrieva, V.G.; Nosova, E.V.; Dergunov, A.D.; Limborska, S.A.; Dergunova, L.V. Genomic Variants and Multilevel Regulation of ABCA1, ABCG1, and SCARB1 Expression in Atherogenesis. J. Cardiovasc. Dev. Dis. 2021, 8, 170. [Google Scholar] [CrossRef]
  10. Sidorkiewicz, M. Is MicroRNA-33 an Appropriate Target in the Treatment of Atherosclerosis? Nutrients 2023, 15, 902. [Google Scholar] [CrossRef]
  11. Tong, K.-L.; Tan, K.-E.; Lim, Y.-Y.; Tien, X.-Y.; Wong, P.-F. CircRNA-MiRNA Interactions in Atherogenesis. Mol. Cell. Biochem. 2022, 477, 2703–2733. [Google Scholar] [CrossRef]
  12. Cheng, C.; Wang, Y.; Xue, Q.; Huang, Y.; Wang, X.; Liao, F.; Miao, C. CircRnas in Atherosclerosis, with Special Emphasis on the Spongy Effect of CircRnas on MiRnas. Cell Cycle 2023, 22, 527–541. [Google Scholar] [CrossRef] [PubMed]
  13. Jiang, Q.; Li, Y.; Wu, Q.; Huang, L.; Xu, J.; Zeng, Q. Pathogenic Role of MicroRNAs in Atherosclerotic Ischemic Stroke: Implications for Diagnosis and Therapy. Genes. Dis. 2022, 9, 682–696. [Google Scholar] [CrossRef] [PubMed]
  14. Fernández-Tussy, P.; Ruz-Maldonado, I.; Fernández-Hernando, C. MicroRNAs and Circular RNAs in Lipoprotein Metabolism. Curr. Atheroscler. Rep. 2021, 23, 33. [Google Scholar] [CrossRef] [PubMed]
  15. Lewis, B.P.; Burge, C.B.; Bartel, D.P. Conserved Seed Pairing, Often Flanked by Adenosines, Indicates That Thousands of Human Genes Are MicroRNA Targets. Cell 2005, 120, 15–20. [Google Scholar] [CrossRef] [Green Version]
  16. Vidigal, J.A.; Ventura, A. The Biological Functions of MiRNAs: Lessons from in Vivo Studies. Trends Cell Biol. 2015, 25, 137–147. [Google Scholar] [CrossRef] [Green Version]
  17. Sallam, T.; Jones, M.; Thomas, B.J.; Wu, X.; Gilliland, T.; Qian, K.; Eskin, A.; Casero, D.; Zhang, Z.; Sandhu, J.; et al. Transcriptional Regulation of Macrophage Cholesterol Efflux and Atherogenesis by a Long Noncoding RNA. Nat. Med. 2018, 24, 304–312. [Google Scholar] [CrossRef] [PubMed]
  18. Meng, X.-D.; Yao, H.-H.; Wang, L.-M.; Yu, M.; Shi, S.; Yuan, Z.-X.; Liu, J. Knockdown of GAS5 Inhibits Atherosclerosis Progression via Reducing EZH2-Mediated ABCA1 Transcription in ApoE-/- Mice. Mol. Ther. Nucleic Acids 2020, 19, 84–96. [Google Scholar] [CrossRef]
  19. Lan, X.; Yan, J.; Ren, J.; Zhong, B.; Li, J.; Li, Y.; Liu, L.; Yi, J.; Sun, Q.; Yang, X.; et al. A Novel Long Noncoding RNA Lnc-HC Binds HnRNPA2B1 to Regulate Expressions of Cyp7a1 and Abca1 in Hepatocytic Cholesterol Metabolism. Hepatology 2016, 64, 58–72. [Google Scholar] [CrossRef]
  20. Statello, L.; Guo, C.-J.; Chen, L.-L.; Huarte, M. Gene Regulation by Long Non-Coding RNAs and Its Biological Functions. Nat. Rev. Mol. Cell Biol. 2021, 22, 159. [Google Scholar] [CrossRef]
  21. Tay, Y.; Rinn, J.; Pandolfi, P.P. The Multilayered Complexity of CeRNA Crosstalk and Competition. Nature 2014, 505, 344–352. [Google Scholar] [CrossRef] [Green Version]
  22. Wang, L.; Meng, X.; Li, G.; Zhou, Q.; Xiao, J. Circular RNAs in Cardiovascular Diseases. Adv. Exp. Med. Biol. 2018, 1087, 191–204. [Google Scholar] [CrossRef]
  23. Li, B.; Li, Y.; Hu, L.; Liu, Y.; Zhou, Q.; Wang, M.; An, Y.; Li, P. Role of Circular RNAs in the Pathogenesis of Cardiovascular Disease. J. Cardiovasc. Transl. Res. 2020, 13, 572–583. [Google Scholar] [CrossRef]
  24. Sun, J.Y.; Shi, Y.; Cai, X.Y.; Liu, J. Potential Diagnostic and Therapeutic Value of Circular RNAs in Cardiovascular Diseases. Cell. Signal 2020, 71, 109604. [Google Scholar] [CrossRef]
  25. Jeck, W.R.; Sharpless, N.E. Detecting and Characterizing Circular RNAs. Nat. Biotechnol. 2014, 32, 453–461. [Google Scholar] [CrossRef] [PubMed]
  26. Memczak, S.; Jens, M.; Elefsinioti, A.; Torti, F.; Krueger, J.; Rybak, A.; Maier, L.; Mackowiak, S.D.; Gregersen, L.H.; Munschauer, M.; et al. Circular RNAs Are a Large Class of Animal RNAs with Regulatory Potency. Nature 2013, 495, 333–338. [Google Scholar] [CrossRef]
  27. Panda, A.C. Circular RNAs Act as MiRNA Sponges. Adv. Exp. Med. Biol. 2018, 1087, 67–79. [Google Scholar] [CrossRef]
  28. Hansen, T.B.; Jensen, T.I.; Clausen, B.H.; Bramsen, J.B.; Finsen, B.; Damgaard, C.K.; Kjems, J. Natural RNA Circles Function as Efficient MicroRNA Sponges. Nature 2013, 495, 384–388. [Google Scholar] [CrossRef] [PubMed]
  29. Joaquim, V.H.A.; Pereira, N.P.; Fernandes, T.; Oliveira, E.M. Circular RNAs as a Diagnostic and Therapeutic Target in Cardiovascular Diseases. Int. J. Mol. Sci. 2023, 24, 2125. [Google Scholar] [CrossRef] [PubMed]
  30. Su, Q.; Lv, X. Revealing New Landscape of Cardiovascular Disease through Circular RNA-MiRNA-MRNA Axis. Genomics 2020, 112, 1680–1685. [Google Scholar] [CrossRef]
  31. Wei, W.; Tang, M.; Wang, Q.; Li, X. Circ_HECW2 Regulates Ox-LDL-Induced Dysfunction of Cardiovascular Endothelial Cells by MiR-942-5p/TLR4 Axis. Clin. Hemorheol. Microcirc. 2022, preprint. [Google Scholar] [CrossRef] [PubMed]
  32. Diener, T.O. Potato Spindle Tuber “Virus”. IV. A Replicating, Low Molecular Weight RNA. Virology 1971, 45, 411–428. [Google Scholar] [CrossRef] [PubMed]
  33. Sanger, H.L.; Klotz, G.; Riesner, D.; Gross, H.J.; Kleinschmidt, A.K. Viroids Are Single-Stranded Covalently Closed Circular RNA Molecules Existing as Highly Base-Paired Rod-like Structures. Proc. Natl. Acad. Sci. USA 1976, 73, 3852–3856. [Google Scholar] [CrossRef]
  34. HSU, M.-T.; COCA-PRADOS, M. Electron Microscopic Evidence for the Circular Form of RNA in the Cytoplasm of Eukaryotic Cells. Nature 1979, 280, 339–340. [Google Scholar] [CrossRef]
  35. Jeck, W.R.; Sorrentino, J.A.; Wang, K.; Slevin, M.K.; Burd, C.E.; Liu, J.; Marzluff, W.F.; Sharpless, N.E. Circular RNAs Are Abundant, Conserved, and Associated with ALU Repeats. RNA 2013, 19, 141–157. [Google Scholar] [CrossRef] [Green Version]
  36. Kristensen, L.S.; Jakobsen, T.; Hager, H.; Kjems, J. The Emerging Roles of CircRNAs in Cancer and Oncology. Nat. Rev. Clin. Oncol. 2022, 19, 188–206. [Google Scholar] [CrossRef] [PubMed]
  37. Filippenkov, I.B.; Kalinichenko, E.O.; Limborska, S.A.; Dergunova, L.V. Circular RNAs-One of the Enigmas of the Brain. Neurogenetics 2017, 18, 1–6. [Google Scholar] [CrossRef]
  38. Bagheri Moghaddam, M.; Maleki, M.; Oveisee, M.; Bagheri Moghaddam, M.; Arabian, M.; Malakootian, M. Circular RNAs: New Players in Cardiomyopathy. Genes 2022, 13, 1537. [Google Scholar] [CrossRef]
  39. Farina, F.M.; Weber, C.; Santovito, D. The Emerging Landscape of Non-Conventional RNA Functions in Atherosclerosis. Atherosclerosis 2023, 374, 74–86. [Google Scholar] [CrossRef]
  40. Li, Z.; Huang, C.; Bao, C.; Chen, L.; Lin, M.; Wang, X.; Zhong, G.; Yu, B.; Hu, W.; Dai, L.; et al. Exon-Intron Circular RNAs Regulate Transcription in the Nucleus. Nat. Struct. Mol. Biol. 2015, 22, 256–264. [Google Scholar] [CrossRef]
  41. Müller, S.; Ebermann, C.; Schnarr, T. Recent Advances in Understanding Circular RNAs. F1000Research 2020, 9, 655. [Google Scholar] [CrossRef]
  42. Wan, L.; Zhang, L.; Fan, K.; Cheng, Z.-X.; Sun, Q.-C.; Wang, J.-J. Circular RNA-ITCH Suppresses Lung Cancer Proliferation via Inhibiting the Wnt/β-Catenin Pathway. Biomed. Res. Int. 2016, 2016, 1579490. [Google Scholar] [CrossRef] [Green Version]
  43. Armakola, M.; Higgins, M.J.; Figley, M.D.; Barmada, S.J.; Scarborough, E.A.; Diaz, Z.; Fang, X.; Shorter, J.; Krogan, N.J.; Finkbeiner, S.; et al. Inhibition of RNA Lariat Debranching Enzyme Suppresses TDP-43 Toxicity in ALS Disease Models. Nat. Genet. 2012, 44, 1302–1309. [Google Scholar] [CrossRef] [Green Version]
  44. Ebert, M.S.; Neilson, J.R.; Sharp, P.A. MicroRNA Sponges: Competitive Inhibitors of Small RNAs in Mammalian Cells. Nat. Methods 2007, 4, 721–726. [Google Scholar] [CrossRef]
  45. Castello, A.; Fischer, B.; Eichelbaum, K.; Horos, R.; Beckmann, B.M.; Strein, C.; Davey, N.E.; Humphreys, D.T.; Preiss, T.; Steinmetz, L.M.; et al. Insights into RNA Biology from an Atlas of Mammalian MRNA-Binding Proteins. Cell 2012, 149, 1393–1406. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Gong, X.; Tian, M.; Cao, N.; Yang, P.; Xu, Z.; Zheng, S.; Liao, Q.; Chen, C.; Zeng, C.; Jose, P.A.; et al. Circular RNA CircEsyt2 Regulates Vascular Smooth Muscle Cell Remodeling via Splicing Regulation. J. Clin. Invest. 2021, 131, e147031. [Google Scholar] [CrossRef]
  47. Zhou, H.; Gan, X.; He, S.; Wang, Y.; Zhang, S.; Chen, J.; Zhou, Y.; Hou, C.; Hua, L.; Zhang, Q.; et al. Identification of Circular RNA BTBD7_hsa_circ_0000563 as a Novel Biomarker for Coronary Artery Disease and the Functional Discovery of BTBD7_hsa_circ_0000563 Based on Peripheral Blood Mononuclear Cells: A Case Control Study. Clin. Proteom. 2022, 19, 37. [Google Scholar] [CrossRef]
  48. Prats, A.-C.; David, F.; Diallo, L.H.; Roussel, E.; Tatin, F.; Garmy-Susini, B.; Lacazette, E. Circular RNA, the Key for Translation. Int. J. Mol. Sci. 2020, 21, 8591. [Google Scholar] [CrossRef] [PubMed]
  49. van Rossum, D.; Verheijen, B.M.; Pasterkamp, R.J. Circular RNAs: Novel Regulators of Neuronal Development. Front. Mol. Neurosci. 2016, 9, 74. [Google Scholar] [CrossRef] [Green Version]
  50. Zhang, Y.; Zhang, X.O.; Chen, T.; Xiang, J.F.; Yin, Q.F.; Xing, Y.H.; Zhu, S.; Yang, L.; Chen, L.L. Circular Intronic Long Noncoding RNAs. Mol. Cell 2013, 51, 792–806. [Google Scholar] [CrossRef] [Green Version]
  51. Kelly, S.; Greenman, C.; Cook, P.R.; Papantonis, A. Exon Skipping Is Correlated with Exon Circularization. J. Mol. Biol. 2015, 427, 2414–2417. [Google Scholar] [CrossRef]
  52. Yao, T.; Chen, Q.; Fu, L.; Guo, J. Circular RNAs: Biogenesis, Properties, Roles, and Their Relationships with Liver Diseases. Hepatol. Res. 2017, 47, 497–504. [Google Scholar] [CrossRef]
  53. Ren, L.; Jiang, Q.; Mo, L.; Tan, L.; Dong, Q.; Meng, L.; Yang, N.; Li, G. Mechanisms of Circular RNA Degradation. Commun. Biol. 2022, 5, 1355. [Google Scholar] [CrossRef] [PubMed]
  54. Zhang, X.O.; Wang, H.B.; Zhang, Y.; Lu, X.; Chen, L.L.; Yang, L. Complementary Sequence-Mediated Exon Circularization. Cell 2014, 159, 134–147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Kristensen, L.S.; Andersen, M.S.; Stagsted, L.V.W.; Ebbesen, K.K.; Hansen, T.B.; Kjems, J. The Biogenesis, Biology and Characterization of Circular RNAs. Nat. Rev. Genet. 2019, 20, 675–691. [Google Scholar] [CrossRef] [PubMed]
  56. Liang, D.; Wilusz, J.E. Short Intronic Repeat Sequences Facilitate Circular RNA Production. Genes. Dev. 2014, 28, 2233–2247. [Google Scholar] [CrossRef] [Green Version]
  57. Ashwal-Fluss, R.; Meyer, M.; Pamudurti, N.R.; Ivanov, A.; Bartok, O.; Hanan, M.; Evantal, N.; Memczak, S.; Rajewsky, N.; Kadener, S. CircRNA Biogenesis Competes with Pre-MRNA Splicing. Mol. Cell 2014, 56, 55–66. [Google Scholar] [CrossRef] [Green Version]
  58. Montañés-Agudo, P.; van der Made, I.; Aufiero, S.; Tijsen, A.J.; Pinto, Y.M.; Creemers, E.E. Quaking Regulates Circular RNA Production in Cardiomyocytes. J. Cell Sci. 2023, 136, jcs261120. [Google Scholar] [CrossRef]
  59. Errichelli, L.; Dini Modigliani, S.; Laneve, P.; Colantoni, A.; Legnini, I.; Capauto, D.; Rosa, A.; De Santis, R.; Scarfò, R.; Peruzzi, G.; et al. FUS Affects Circular RNA Expression in Murine Embryonic Stem Cell-Derived Motor Neurons. Nat. Commun. 2017, 8, 14741. [Google Scholar] [CrossRef] [Green Version]
  60. Dong, W.; Dai, Z.H.; Liu, F.C.; Guo, X.G.; Ge, C.M.; Ding, J.; Liu, H.; Yang, F. The RNA-Binding Protein RBM3 Promotes Cell Proliferation in Hepatocellular Carcinoma by Regulating Circular RNA SCD-CircRNA 2 Production. EBioMedicine 2019, 45, 155–167. [Google Scholar] [CrossRef] [Green Version]
  61. Hsiao, K.Y.; Sun, H.S.; Tsai, S.J. Circular RNA—New Member of Noncoding RNA with Novel Functions. Exp. Biol. Med. 2017, 242, 1136–1141. [Google Scholar] [CrossRef] [Green Version]
  62. Liang, D.; Tatomer, D.C.; Luo, Z.; Wu, H.; Yang, L.; Chen, L.L.; Cherry, S.; Wilusz, J.E. The Output of Protein-Coding Genes Shifts to Circular RNAs When the Pre-MRNA Processing Machinery Is Limiting. Mol. Cell 2017, 68, 940–954.e3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Kokot, K.E.; Kneuer, J.M.; John, D.; Rebs, S.; Möbius-Winkler, M.N.; Erbe, S.; Müller, M.; Andritschke, M.; Gaul, S.; Sheikh, B.N.; et al. Reduction of A-to-I RNA Editing in the Failing Human Heart Regulates Formation of Circular RNAs. Basic Res. Cardiol. 2022, 117, 32. [Google Scholar] [CrossRef]
  64. Aktaş, T.; Ilik, I.A.; Maticzka, D.; Bhardwaj, V.; Pessoa Rodrigues, C.; Mittler, G.; Manke, T.; Backofen, R.; Akhtar, A. DHX9 Suppresses RNA Processing Defects Originating from the Alu Invasion of the Human Genome. Nature 2017, 544, 115–119. [Google Scholar] [CrossRef]
  65. Eleazer, R.; De Silva, K.; Andreeva, K.; Jenkins, Z.; Osmani, N.; Rouchka, E.C.; Fondufe-Mittendorf, Y. PARP1 Regulates Circular RNA Biogenesis Though Control of Transcriptional Dynamics. Cells 2023, 12, 1160. [Google Scholar] [CrossRef]
  66. Li, X.; Zhang, J.L.; Lei, Y.N.; Liu, X.Q.; Xue, W.; Zhang, Y.; Nan, F.; Gao, X.; Zhang, J.; Wei, J.; et al. Linking Circular Intronic RNA Degradation and Function in Transcription by RNase H1. Sci. China Life Sci. 2021, 64, 1795–1809. [Google Scholar] [CrossRef] [PubMed]
  67. Zheng, Z.M. Circular RNAs and RNase L in PKR Activation and Virus Infection. Cell Biosci. 2019, 9, 43. [Google Scholar] [CrossRef]
  68. Liu, C.X.; Li, X.; Nan, F.; Jiang, S.; Gao, X.; Guo, S.K.; Xue, W.; Cui, Y.; Dong, K.; Ding, H.; et al. Structure and Degradation of Circular RNAs Regulate PKR Activation in Innate Immunity. Cell 2019, 177, 865–880.e21. [Google Scholar] [CrossRef]
  69. Park, O.H.; Ha, H.; Lee, Y.; Boo, S.H.; Kwon, D.H.; Song, H.K.; Kim, Y.K. Endoribonucleolytic Cleavage of M6A-Containing RNAs by RNase P/MRP Complex. Mol. Cell 2019, 74, 494–507.e8. [Google Scholar] [CrossRef] [PubMed]
  70. Fischer, J.W.; Busa, V.F.; Shao, Y.; Leung, A.K.L. Structure-Mediated RNA Decay by UPF1 and G3BP1. Mol. Cell 2020, 78, 70–84.e6. [Google Scholar] [CrossRef]
  71. Piwecka, M.; Glažar, P.; Hernandez-Miranda, L.R.; Memczak, S.; Wolf, S.A.; Rybak-Wolf, A.; Filipchyk, A.; Klironomos, F.; Jara, C.A.C.; Fenske, P.; et al. Loss of a Mammalian Circular RNA Locus Causes MiRNA Deregulation and Affects Brain Function. Science 2017, 357, eaam8526. [Google Scholar] [CrossRef] [Green Version]
  72. Zhou, M.; Xiao, M.S.; Li, Z.; Huang, C. New Progresses of Circular RNA Biology: From Nuclear Export to Degradation. RNA Biol. 2021, 18, 1365–1373. [Google Scholar] [CrossRef]
  73. Guo, J.U.; Agarwal, V.; Guo, H.; Bartel, D.P. Expanded Identification and Characterization of Mammalian Circular RNAs. Genome Biol. 2014, 15, 409. [Google Scholar] [CrossRef]
  74. Xu, J.-L.; Xu, W.-X.; Tang, J.-H. Exosomal CircRNAs: A New Communication Method in Cancer. Am. J. Transl. Res. 2021, 13, 12913. [Google Scholar]
  75. Lasda, E.; Parker, R. Circular RNAs Co-Precipitate with Extracellular Vesicles: A Possible Mechanism for CircRNA Clearance. PLoS ONE 2016, 11, e0148407. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Yáñez-Mó, M.; Siljander, P.R.M.; Andreu, Z.; Zavec, A.B.; Borràs, F.E.; Buzas, E.I.; Buzas, K.; Casal, E.; Cappello, F.; Carvalho, J.; et al. Biological Properties of Extracellular Vesicles and Their Physiological Functions. J. Extracell. Vesicles 2015, 4, 27066. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Xiong, Y.; Song, J.; Huang, X.; Pan, Z.; Goldbrunner, R.; Stavrinou, L.; Lin, S.; Hu, W.; Zheng, F.; Stavrinou, P. Exosomes Derived From Mesenchymal Stem Cells: Novel Effects in the Treatment of Ischemic Stroke. Front. Neurosci. 2022, 16, 899887. [Google Scholar] [CrossRef] [PubMed]
  78. Ji, W.F.; Chen, J.X.; He, S.; Zhou, Y.Q.; Hua, L.; Hou, C.; Zhang, S.; Gan, X.K.; Wang, Y.J.; Zhou, H.X.; et al. Characteristics of Circular Rnas Expression of Peripheral Blood Mononuclear Cells in Humans with Coronary Artery Disease. Physiol. Genom. 2021, 53, 349–357. [Google Scholar] [CrossRef]
  79. Tan, W.L.W.; Lim, B.T.S.; Anene-Nzelu, C.G.O.; Ackers-Johnson, M.; Dashi, A.; See, K.; Tiang, Z.; Lee, D.P.; Chua, W.W.; Luu, T.D.A.; et al. A Landscape of Circular RNA Expression in the Human Heart. Cardiovasc. Res. 2017, 113, 298–309. [Google Scholar] [CrossRef]
  80. Wei, L.; Yu, Z.; Liu, L.; Zhou, Y.; Bai, X.; Wang, L.; Bai, M.; Sun, S. Integrated Analysis of the CircRNA-Based CeRNA Network in Renal Fibrosis Induced by Ischemia Reperfusion Injury. Front. Genet. 2022, 12, 793182. [Google Scholar] [CrossRef]
  81. Verduci, L.; Tarcitano, E.; Strano, S.; Yarden, Y.; Blandino, G. CircRNAs: Role in Human Diseases and Potential Use as Biomarkers. Cell Death Dis. 2021, 12, 468. [Google Scholar] [CrossRef] [PubMed]
  82. Lim, T.B.; Lavenniah, A.; Foo, R.S.Y. Circles in the Heart and Cardiovascular System. Cardiovasc. Res. 2020, 116, 269–278. [Google Scholar] [CrossRef]
  83. Zhang, C.; Ge, S.; Gong, W.; Xu, J.; Guo, Z.; Liu, Z.; Gao, X.; Wei, X.; Ge, S. LncRNA ANRIL Acts as a Modular Scaffold of WDR5 and HDAC3 Complexes and Promotes Alteration of the Vascular Smooth Muscle Cell Phenotype. Cell Death Dis. 2020, 11, 435. [Google Scholar] [CrossRef] [PubMed]
  84. Chen, S.; Sun, L.; Zhang, J.; Zhang, L.; Liu, X. Oxygenized Low-Density Lipoprotein-Induced ASMC Dysregulation Depends on Circ_0000345-Mediated Regulatory Mechanism. J. Atheroscler. Thromb. 2022, 29, 63327. [Google Scholar] [CrossRef]
  85. Wang, Y.; Liu, P.; Chen, X.; Yang, W. Circ_CHMP5 Aggravates Oxidized Low-Density Lipoprotein-Induced Damage to Human Umbilical Vein Endothelial Cells through MiR-516b-5p/TGFβR2 Axis. Clin. Hemorheol. Microcirc. 2023, preprint. [Google Scholar] [CrossRef]
  86. Lin, H.; Gao, D.; Wang, S.; Wang, Z.; Guan, H.; Wang, Y.; Zhou, Y. Inhibition of Circ_0000231 Suppresses Oxidized Low Density Lipoprotein-Induced Apoptosis, Autophagy and Inflammation in Human Umbilical Vein Endothelial Cells by Regulating MiR-590-5p/PDCD4 Axis. Clin. Hemorheol. Microcirc. 2023, preprint. [Google Scholar] [CrossRef]
  87. Moore, K.J.; Tabas, I. Macrophages in the Pathogenesis of Atherosclerosis. Cell 2011, 145, 341–355. [Google Scholar] [CrossRef] [Green Version]
  88. Hansson, G.K.; Hermansson, A. The Immune System in Atherosclerosis. Nat. Immunol. 2011, 12, 204–212. [Google Scholar] [CrossRef]
  89. Lusis, A.J. Atherosclerosis. Nature 2000, 407, 233–241. [Google Scholar] [CrossRef] [PubMed]
  90. Zernecke, A.; Weber, C. Chemokines in the Vascular Inflammatory Response of Atherosclerosis. Cardiovasc. Res. 2010, 86, 192–201. [Google Scholar] [CrossRef]
  91. Brunetti, N.D.; Salvemini, G.; Cuculo, A.; Ruggiero, A.; De Gennaro, L.; Gaglione, A.; Di Biase, M. Coronary Artery Ectasia Is Related to Coronary Slow Flow and Inflammatory Activation. Atherosclerosis 2014, 233, 636–640. [Google Scholar] [CrossRef]
  92. Shen, L.; Hu, Y.; Lou, J.; Yin, S.; Wang, W.; Wang, Y.; Xia, Y.; Wu, W. CircRNA-0044073 Is Upregulated in Atherosclerosis and Increases the Proliferation and Invasion of Cells by Targeting MiR-107. Mol. Med. Rep. 2019, 19, 3923–3932. [Google Scholar] [CrossRef] [PubMed]
  93. Zhang, S.; Wang, W.; Wu, X.; Zhou, X. Regulatory Roles of Circular RNAs in Coronary Artery Disease. Mol. Ther. Nucleic Acids 2020, 21, 172–179. [Google Scholar] [CrossRef] [PubMed]
  94. Long, Q.; Lv, B.; Jiang, S.; Lin, J. The Landscape of Circular RNAs in Cardiovascular Diseases. Int. J. Mol. Sci. 2023, 24, 4571. [Google Scholar] [CrossRef]
  95. Pan, R.-Y.; Liu, P.; Zhou, H.-T.; Sun, W.-X.; Song, J.; Shu, J.; Cui, G.-J.; Yang, Z.-J.; Jia, E.-Z. Circular RNAs Promote TRPM3 Expression by Inhibiting Hsa-MiR-130a-3p in Coronary Artery Disease Patients. Oncotarget 2017, 8, 60280–60290. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Pan, R.-Y.; Zhao, C.-H.; Yuan, J.-X.; Zhang, Y.-J.; Jin, J.-L.; Gu, M.-F.; Mao, Z.-Y.; Sun, H.-J.; Jia, Q.-W.; Ji, M.-Y.; et al. Circular RNA Profile in Coronary Artery Disease. Am. J. Transl. Res. 2019, 11, 7115. [Google Scholar]
  97. Hou, C.; Gu, L.; Guo, Y.; Zhou, Y.; Hua, L.; Chen, J.; He, S.; Zhang, S.; Jia, Q.; Zhao, C.; et al. Association between Circular RNA Expression Content and Severity of Coronary Atherosclerosis in Human Coronary Artery. J. Clin. Lab. Anal. 2020, 34, e23552. [Google Scholar] [CrossRef]
  98. Yang, L.; Chen, W.; Li, B.; Hu, Y.; Lu, H.; Zhang, P.; Yang, H.; Zhang, M.; Pan, D. Circular RNA Circ_0026218 Suppressed Atherosclerosis Progression via MiR-338-3p/SIRT6 Axis. Biomed. Res. Int. 2023, 2023, 5647758. [Google Scholar] [CrossRef] [PubMed]
  99. Yu, L.; Ma, W.; Song, B.; Wang, S.; Li, X.; Wang, Z. Hsa_circ_0030042 Ameliorates Oxidized Low-Density Lipoprotein-Induced Endothelial Cell Injury via the MiR-616-3p/RFX7 Axis. Int. Heart J. 2022, 63, 22–065. [Google Scholar] [CrossRef]
  100. Zhang, W.-B.; Qi, Y.-F.; Xiao, Z.-X.; Chen, H.; Liu, S.-H.; Li, Z.-Z.; Zeng, Z.-F.; Wu, H.-F. CircHIPK3 Regulates Vascular Smooth Muscle Cell Calcification Via the MiR-106a-5p/MFN2 Axis. J. Cardiovasc. Transl. Res. 2022, 15, 1315–1326. [Google Scholar] [CrossRef]
  101. WEI, M.Y.; LV, R.R.; TENG, Z. Circular RNA CircHIPK3 as a Novel CircRNA Regulator of Autophagy and Endothelial Cell Dysfunction in Atherosclerosis. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 12849–12858. [Google Scholar] [CrossRef] [PubMed]
  102. Kang, L.; Jia, H.; Huang, B.; Lu, S.; Chen, Z.; Shen, J.; Zou, Y.; Wang, C.; Sun, Y. Identification of Differently Expressed MRNAs in Atherosclerosis Reveals CDK6 Is Regulated by CircHIPK3/MiR-637 Axis and Promotes Cell Growth in Human Vascular Smooth Muscle Cells. Front. Genet. 2021, 12, 596169. [Google Scholar] [CrossRef]
  103. Ji, N.; Wang, Y.; Gong, X.; Ni, S.; Zhang, H. CircMTO1 Inhibits Ox-LDL-Stimulated Vascular Smooth Muscle Cell Proliferation and Migration via Regulating the MiR-182-5p/RASA1 Axis. Mol. Med. 2021, 27, 73. [Google Scholar] [CrossRef]
  104. Wei, Z.; Ran, H.; Yang, C. CircRSF1 Contributes to Endothelial Cell Growth, Migration and Tube Formation under Ox-LDL Stress through Regulating MiR-758/CCND2 Axis. Life Sci. 2020, 259, 118241. [Google Scholar] [CrossRef] [PubMed]
  105. Tiliwaldi, H.; Tursun, A.; Tohti, A.; Mamatzunun, M.; Wu, Z. Circ_0000345 Protects Endothelial Cells From Oxidized Low-Density Lipoprotein-Induced Injury by MiR-129-5p/Ten-Eleven Translocation Axis. J. Cardiovasc. Pharmacol. 2021, 77, 603–613. [Google Scholar] [CrossRef]
  106. Yuan, R.; Xin, Q.; Ma, X.; Yu, M.; Miao, Y.; Chen, K.; Cong, W. Identification of a Novel Angiogenesis Signalling CircSCRG1/MiR-1268b/NR4A1 Pathway in Atherosclerosis and the Regulatory Effects of TMP-PF In Vitro. Molecules 2023, 28, 1271. [Google Scholar] [CrossRef] [PubMed]
  107. Wang, Y.; Chen, X.; Lu, Z.; Lai, C. Circ_0093887 Regulated Ox-LDL Induced Human Aortic Endothelial Cells Viability, Apoptosis, and Inflammation through Modulating MiR-758-3p/BAMBI Axis in Atherosclerosis. Clin. Hemorheol. Microcirc. 2022, 81, 343–358. [Google Scholar] [CrossRef] [PubMed]
  108. Gao, Y.; Li, G.; Fan, S.; Wang, Y.; Wei, H.; Li, M.; Li, X. Circ_0093887 Upregulates CCND2 and SUCNR1 to Inhibit the Ox-LDL-Induced Endothelial Dysfunction in Atherosclerosis by Functioning as a MiR-876-3p Sponge. Clin. Exp. Pharmacol. Physiol. 2021, 48, 1137–1149. [Google Scholar] [CrossRef] [PubMed]
  109. Kong, P.; Yu, Y.; Wang, L.; Dou, Y.-Q.; Zhang, X.-H.; Cui, Y.; Wang, H.-Y.; Yong, Y.-T.; Liu, Y.-B.; Hu, H.-J.; et al. Circ-Sirt1 Controls NF-ΚB Activation via Sequence-Specific Interaction and Enhancement of SIRT1 Expression by Binding to MiR-132/212 in Vascular Smooth Muscle Cells. Nucleic Acids Res. 2019, 47, 3580–3593. [Google Scholar] [CrossRef] [Green Version]
  110. Yang, Z.; Liang, X.; Yang, L. Circular RNA Circ_0001445 Alleviates the Ox-LDL-Induced Endothelial Injury in Human Primary Aortic Endothelial Cells through Regulating ABCG1 via Acting as a Sponge of MiR-208b-5p. Gen. Thorac. Cardiovasc. Surg. 2022, 70, 779–792. [Google Scholar] [CrossRef]
  111. Ryu, J.; Choe, N.; Kwon, D.-H.; Shin, S.; Lim, Y.-H.; Yoon, G.; Kim, J.H.; Kim, H.S.; Lee, I.-K.; Ahn, Y.; et al. Circular RNA CircSmoc1-2 Regulates Vascular Calcification by Acting as a MiR-874-3p Sponge in Vascular Smooth Muscle Cells. Mol. Ther. Nucleic Acids 2022, 27, 645–655. [Google Scholar] [CrossRef]
  112. Kou, L.; Yang, N.; Dong, B.; Yang, J.; Song, Y.; Li, Y.; Qin, Q. Circular RNA Testis-Expressed 14 Overexpression Induces Apoptosis and Suppresses Migration of Ox-LDL-Stimulated Vascular Smooth Muscle Cells via Regulating the MicroRNA 6509-3p/Thanatos-Associated Domain-Containing Apoptosis-Associated Protein 1 Axis. Bioengineered 2022, 13, 13150–13161. [Google Scholar] [CrossRef] [PubMed]
  113. Wang, P.; Zhang, H.; Wang, Y. Circ_0003423 Alleviates Oxidized Low-Density Lipoprotein-Induced Endothelial Cell Injury by Sponging MiR-142-3p and Activating Sirtuin 3/Superoxide Dismutase 2 Pathway. J. Surg. Res. 2022, 277, 384–397. [Google Scholar] [CrossRef] [PubMed]
  114. Vilades, D.; Martínez-Camblor, P.; Ferrero-Gregori, A.; Bär, C.; Lu, D.; Xiao, K.; Vea, À.; Nasarre, L.; Sanchez Vega, J.; Leta, R.; et al. Plasma Circular RNA Hsa_circ_0001445 and Coronary Artery Disease: Performance as a Biomarker. FASEB J. 2020, 34, 4403–4414. [Google Scholar] [CrossRef] [Green Version]
  115. Cai, Y.; Xu, L.; Xu, C.; Wang, Y.; Fan, C. Hsa_circ_0001445 Inhibits Ox-LDL-Induced HUVECs Inflammation, Oxidative Stress and Apoptosis by Regulating MiRNA-640. Perfusion 2022, 37, 86–94. [Google Scholar] [CrossRef]
  116. Dinh, P.; Peng, J.; Tran, T.; Wu, D.; Tran, C.; Dinh, T.; Pan, S. Identification of Hsa_circ_0001445 of a Novel CircRNA-MiRNA-MRNA Regulatory Network as Potential Biomarker for Coronary Heart Disease. Front. Cardiovasc. Med. 2023, 10, 1104223. [Google Scholar] [CrossRef]
  117. Li, R.; Jiang, Q.; Zheng, Y. Circ_0002984 Induces Proliferation, Migration and Inflammation Response of VSMCs Induced by Ox-LDL through MiR-326-3p/VAMP3 Axis in Atherosclerosis. J. Cell Mol. Med. 2021, 25, 8028–8038. [Google Scholar] [CrossRef]
  118. Wang, Y.; Pei, W.; Lu, P. Circ_ARHGAP32 Acts as MiR-665 Sponge to Upregulate FGF2 to Promote Ox-LDL Induced Vascular Smooth Muscle Cells Proliferation and Migration. Clin. Hemorheol. Microcirc. 2022, 82, 169–182. [Google Scholar] [CrossRef] [PubMed]
  119. Chen, M.; Shi, S.; Zhao, J.; Pan, Q.; Huang, C.; Shen, Q.; Liu, Z. Propofol Inhibits Cell Apoptosis and Inflammatory Response in Ox-LDL-Induced Human Umbilical Vein Endothelial Cells through the Modulation of the Circ_0003645/MiR-149-3p/TRAF7 Axis. Clin. Hemorheol. Microcirc. 2022, 84, 1–18. [Google Scholar] [CrossRef] [PubMed]
  120. Chen, T.; Li, L.; Ye, B.; Chen, W.; Zheng, G.; Xie, H.; Guo, Y. Knockdown of Hsa_circ_0005699 Attenuates Inflammation and Apoptosis Induced by Ox-LDL in Human Umbilical Vein Endothelial Cells through Regulation of the MiR-450b-5p/NFKB1 Axis. Mol. Med. Rep. 2022, 26, 290. [Google Scholar] [CrossRef]
  121. Geng, H.-H.; Li, R.; Su, Y.-M.; Xiao, J.; Pan, M.; Cai, X.-X.; Ji, X.-P. The Circular RNA Cdr1as Promotes Myocardial Infarction by Mediating the Regulation of MiR-7a on Its Target Genes Expression. PLoS ONE 2016, 11, e0151753. [Google Scholar] [CrossRef]
  122. Huang, S.; Zeng, Z.; Sun, Y.; Cai, Y.; Xu, X.; Li, H.; Wu, S. Association Study of Hsa_circ_0001946, Hsa-MiR-7-5p and PARP1 in Coronary Atherosclerotic Heart Disease. Int. J. Cardiol. 2021, 328, 1–7. [Google Scholar] [CrossRef]
  123. Liu, J.; Zhang, X.; Yu, Z.; Zhang, T. Circ_0026218 Ameliorates Oxidized Low-Density Lipoprotein-Induced Vascular Endothelial Cell Dysfunction by Regulating MiR-188-3p/TLR4/NF-ΚB Pathway. Cardiovasc. Drugs Ther. 2022; online ahead of print. [Google Scholar] [CrossRef]
  124. Li, Y.; Wang, B. Circular RNA CircCHFR Downregulation Protects against Oxidized Low-Density Lipoprotein-Induced Endothelial Injury via Regulation of MicroRNA-15b-5p/Growth Arrest and DNA Damage Inducible Gamma. Bioengineered 2022, 13, 4481–4492. [Google Scholar] [CrossRef] [PubMed]
  125. Yang, L.; Yang, F.; Zhao, H.; Wang, M.; Zhang, Y. Circular RNA CircCHFR Facilitates the Proliferation and Migration of Vascular Smooth Muscle via MiR-370/FOXO1/Cyclin D1 Pathway. Mol. Ther. Nucleic Acids 2019, 16, 434–441. [Google Scholar] [CrossRef] [Green Version]
  126. He, D.; Li, Z.; Chen, Y.; Huang, M. Circular RNA Circ_0029589 Promotes Ox-LDL-Induced Endothelial Cell Injury through Regulating RAB22A by Serving as a Sponge of MiR-1197. Clin. Hemorheol. Microcirc. 2023, 83, 359–376. [Google Scholar] [CrossRef]
  127. Li, X.; Kang, X.; Di, Y.; Sun, S.; Yang, L.; Wang, B.; Ji, Z. CircCHMP5 Contributes to Ox-LDL-Induced Endothelial Cell Injury Through the Regulation of MiR-532-5p/ROCK2 Axis. Cardiovasc. Drugs Ther. 2022. online ahead of print. [Google Scholar] [CrossRef] [PubMed]
  128. Ye, M.; Ni, Q.; Wang, H.; Wang, Y.; Yao, Y.; Li, Y.; Wang, W.; Yang, S.; Chen, J.; Lv, L.; et al. CircRNA CircCOL1A1 Acts as a Sponge of MiR-30a-5p to Promote Vascular Smooth Cell Phenotype Switch through Regulation of Smad1 Expression. Thromb. Haemost. 2023, 123, 097–107. [Google Scholar] [CrossRef]
  129. Wang, K.; Bai, X.; Mei, L.; Miao, Y.; Jin, F. CircRNA_0050486 Promotes Cell Apoptosis and Inflammation by Targeting MiR-1270 in Atherosclerosis. Ann. Transl. Med. 2022, 10, 905. [Google Scholar] [CrossRef] [PubMed]
  130. Zhang, P.; Wang, W.; Li, M. Role and Mechanism of Circular RNA Circ_0050486 in Regulating Oxidized Low-Density Lipoprotein-Induced Injury in Endothelial Cells. Clin. Hemorheol. Microcirc. 2022, 82, 107–124. [Google Scholar] [CrossRef] [PubMed]
  131. Liu, F.; Gao, B.; Wang, Y. CircIRAK1 Aggravates Ox-LDL-Induced Endothelial Cell Injury in Atherosclerosis via TRIM14 Upregulation by Binding to MiR-330-5p1. Clin. Hemorheol. Microcirc. 2022, preprint. [Google Scholar] [CrossRef] [PubMed]
  132. Zhu, L.; Zhao, P.; Meng, X.; Jin, H.; Tuo, B. Circ_0091822 Aggravates Ox-LDL-Induced Endothelial Cell Injury through Targeting the MiR-661/RAB22A Axis. Clin. Hemorheol. Microcirc. 2022, 83, 47–59. [Google Scholar] [CrossRef] [PubMed]
  133. Zhu, J.; Chen, Z.; Peng, X.; Zheng, Z.; Le, A.; Guo, J.; Ma, L.; Shi, H.; Yao, K.; Zhang, S.; et al. Extracellular Vesicle-Derived CircITGB1 Regulates Dendritic Cell Maturation and Cardiac Inflammation via MiR-342-3p/NFAM1. Oxid. Med. Cell. Longev. 2022, 2022, 8392313. [Google Scholar] [CrossRef]
  134. Li, F.; Chen, Y.; He, Z.; Wang, C.; Wang, X.; Pan, G.; Peng, J.Y.; Chen, Q.; Wang, X. Hsa_circ_0001879 Promotes the Progression of Atherosclerosis by Regulating the Proliferation and Migration of Oxidation of Low Density Lipoprotein (Ox-LDL)-Induced Vascular Endothelial Cells via the MiR-6873-5p-HDAC9 Axis. Bioengineered 2021, 12, 10420–10429. [Google Scholar] [CrossRef]
  135. Xiong, F.; Mao, R.; Zhang, L.; Zhao, R.; Tan, K.; Liu, C.; Xu, J.; Du, G.; Zhang, T. CircNPHP4 in Monocyte-Derived Small Extracellular Vesicles Controls Heterogeneous Adhesion in Coronary Heart Atherosclerotic Disease. Cell Death Dis. 2021, 12, 948. [Google Scholar] [CrossRef]
  136. Jing, B.; Hui, Z. Circular RNA_0033596 Aggravates Endothelial Cell Injury Induced by Oxidized Low-Density Lipoprotein via MicroRNA-217-5p /Chloride Intracellular Channel 4 Axis. Bioengineered 2022, 13, 3410–3421. [Google Scholar] [CrossRef]
  137. Hou, X.; Dai, H.; Zheng, Y. Circular RNA Hsa_circ_0008896 Accelerates Atherosclerosis by Promoting the Proliferation, Migration and Invasion of Vascular Smooth Muscle Cells via Hsa-MiR-633/CDC20B (Cell Division Cycle 20B) Axis. Bioengineered 2022, 13, 5987–5998. [Google Scholar] [CrossRef] [PubMed]
  138. Zhang, L.L. CircRNA-PTPRA Promoted the Progression of Atherosclerosis through Sponging with MiR-636 and Upregulating the Transcription Factor SP1. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 12437–12449. [Google Scholar] [CrossRef]
  139. Mei, R.; Wu, M.; Ren, F. Knockdown of Circ_0002194 Protects against Oxidized Low-Density Lipoprotein-Induced Cell Damage via the Regulation of the MiR-637/PACS2 Axis in Human Vascular Endothelial Cells. Interact. Cardiovasc. Thorac. Surg. 2022, 35, ivac210. [Google Scholar] [CrossRef]
  140. Huang, H.; Huang, X.; Yu, H.; Xue, Y.; Zhu, P. Circular RNA Circ-RELL1 Regulates Inflammatory Response by MiR-6873-3p/MyD88/NF-ΚB Axis in Endothelial Cells. Biochem. Biophys. Res. Commun. 2020, 525, 512–519. [Google Scholar] [CrossRef]
  141. Lin, D.-S.; Zhang, C.-Y.; Li, L.; Ye, G.-H.; Jiang, L.-P.; Jin, Q. Circ_ROBO2/MiR-149 Axis Promotes the Proliferation and Migration of Human Aortic Smooth Muscle Cells by Activating NF-ΚB Signaling. Cytogenet. Genome Res. 2021, 161, 414–424. [Google Scholar] [CrossRef]
  142. Mao, X.; Wang, L.; Chen, C.; Tao, L.; Ren, S.; Zhang, L. Circ_0124644 Enhances Ox-LDL-Induced Cell Damages in Human Umbilical Vein Endothelial Cells through Upregulating FOXO4 by Sponging MiR-370-3p. Clin. Hemorheol. Microcirc. 2022, 81, 135–147. [Google Scholar] [CrossRef]
  143. Ye, Q.; Ju, C.; Ye, Z.; Tong, J. Circ_ROBO2/MiR-186-5p/TRIM14 Axis Regulates Oxidized Low-Density Lipoprotein-Induced Cardiac Microvascular Endothelial Cell Injury. Regen. Ther. 2022, 20, 138–146. [Google Scholar] [CrossRef] [PubMed]
  144. He, Q.; Shao, D.; Hao, S.; Yuan, Y.; Liu, H.; Liu, F.; Mu, Q. CircSCAP Aggravates Oxidized Low-Density Lipoprotein-Induced Macrophage Injury by Upregulating PDE3B by MiR-221-5p in Atherosclerosis. J. Cardiovasc. Pharmacol. 2021, 78, e749–e760. [Google Scholar] [CrossRef] [PubMed]
  145. Du, N.; Li, M.; Yang, D. Hsa_circRNA_102541 Regulates the Development of Atherosclerosis by Targeting MiR-296-5p/PLK1 Pathway. Ir. J. Med. Sci. 2022, 191, 1153–1159. [Google Scholar] [CrossRef] [PubMed]
  146. Zhang, Y.; Wang, S.; Guo, S.; Zhang, X.; Yang, C.; Su, G.; Wan, J. Circ_0004104 Participates in the Regulation of Ox-LDL-Induced Endothelial Cells Injury via MiR-942-5p/ROCK2 Axis. BMC Cardiovasc. Disord. 2022, 22, 517. [Google Scholar] [CrossRef]
  147. Guan, Z.; Lu, R.; Sun, Y.; Wang, X.; Yu, C.; Song, T. Regulation of Oxidized LDL-Induced Proliferation and Migration in Human Vascular Smooth Muscle Cells by a Novel Circ_0007478/MiR-638/ROCK2 CeRNA Network. Vasc. Med. 2023, 28, 6–17. [Google Scholar] [CrossRef]
  148. Ye, B.; Liang, X.; Zhao, Y.; Cai, X.; Wang, Z.; Lin, S.; Wang, W.; Shan, P.; Huang, W.; Huang, Z. Hsa_circ_0007478 Aggravates NLRP3 Inflammasome Activation and Lipid Metabolism Imbalance in Ox-LDL-Stimulated Macrophage via MiR-765/EFNA3 Axis. Chem. Biol. Interact. 2022, 368, 110195. [Google Scholar] [CrossRef] [PubMed]
  149. Lin, J.; Liu, C.; Xu, J.; Li, S.; Dai, D.; Zhang, L.; Yonghui, P. Circ_0021155 Can Participate in the Phenotypic Transformation of Human Vascular Smooth Muscle Cells via the MiR-4459/TRPM7 Axis. Biochem. Biophys. Res. Commun. 2022, 630, 133–142. [Google Scholar] [CrossRef]
  150. Chen, M.; Li, F.; Jiang, Q.; Zhang, W.; Li, Z.; Tang, W. Role of MiR-181b/Notch1 Axis in Circ_TNPO1 Promotion of Proliferation and Migration of Atherosclerotic Vascular Smooth Muscle Cells. J. Healthc. Eng. 2022, 2022, 4086935. [Google Scholar] [CrossRef]
  151. Zhang, Y.; Zhang, C.; Chen, Z.; Wang, M. Blocking Circ_UBR4 Suppressed Proliferation, Migration, and Cell Cycle Progression of Human Vascular Smooth Muscle Cells in Atherosclerosis. Open Life Sci. 2021, 16, 419–430. [Google Scholar] [CrossRef] [PubMed]
  152. Ding, P.; Ding, Y.; Tian, Y.; Lei, X. Circular RNA Circ_0010283 Regulates the Viability and Migration of Oxidized Low-density Lipoprotein-induced Vascular Smooth Muscle Cells via an MiR-370-3p/HMGB1 Axis in Atherosclerosis. Int. J. Mol. Med. 2020, 46, 1399–1408. [Google Scholar] [CrossRef]
  153. Feng, Z.; Zhu, Y.; Zhang, J.; Yang, W.; Chen, Z.; Li, B. Hsa-Circ_0010283 Regulates Oxidized Low-Density Lipoprotein-Induced Proliferation and Migration of Vascular Smooth Muscle Cells by Targeting the MiR-133a-3p/Pregnancy-Associated Plasma Protein A Axis. Circ. J. 2020, 84, 2259–2269. [Google Scholar] [CrossRef] [PubMed]
  154. Zhang, M.; Zhu, Y.; Zhu, J.; Xie, Y.; Wu, R.; Zhong, J.; Qiu, Z.; Jiang, L. Circ_0086296 Induced Atherosclerotic Lesions via the IFIT1/STAT1 Feedback Loop by Sponging MiR-576-3p. Cell. Mol. Biol. Lett. 2022, 27, 80. [Google Scholar] [CrossRef]
  155. Zhao, Q.; Lu, Y.-H.; Wang, X.; Zhang, X.-J. Circ_USP36/MiR-182-5p/KLF5 Axis Regulates the Ox-LDL-Induced Injury in Human Umbilical Vein Smooth Muscle Cells. Am. J. Transl. Res. 2020, 12, 7855–7869. [Google Scholar]
  156. Wan, H.; You, T.; Luo, W. Circ_0003204 Regulates Cell Growth, Oxidative Stress, and Inflammation in Ox-LDL-Induced Vascular Endothelial Cells via Regulating MiR-942-5p/HDAC9 Axis. Front. Cardiovasc. Med. 2021, 8, 646832. [Google Scholar] [CrossRef]
  157. Lei, X.; Yang, Y. Oxidized Low-Density Lipoprotein Contributes to Injury of Endothelial Cells via the Circ_0090231/MiR-9-5p/TXNIP Axis. Cent. Eur. J. Immunol. 2022, 47, 41–57. [Google Scholar] [CrossRef]
  158. Peng, H.; Sun, J.; Li, Y.; Zhang, Y.; Zhong, Y. Circ-USP9X Inhibition Reduces Oxidized Low-Density Lipoprotein–Induced Endothelial Cell Injury via the MicroRNA 599/Chloride Intracellular Channel 4 Axis. J. Cardiovasc. Pharmacol. 2021, 78, 560–571. [Google Scholar] [CrossRef]
  159. Wen, Y.; Chun, Y.; Lian, Z.; Yong, Z.; Lan, Y.; Huan, L.; Xi, C.; Juan, L.; Qing, Z.; Jia, C.; et al. CircRNA-0006896-miR1264-DNMT1 Axis Plays an Important Role in Carotid Plaque Destabilization by Regulating the Behavior of Endothelial Cells in Atherosclerosis. Mol. Med. Rep. 2021, 23, 311. [Google Scholar] [CrossRef]
  160. Chen, W.; Liu, Y.; Li, L.; Liang, B.; Wang, S.; Xu, X.; Xing, D.; Wu, X. The Potential Role and Mechanism of CircRNAs in Foam Cell Formation. Noncoding RNA Res. 2023, 8, 315–325. [Google Scholar] [CrossRef] [PubMed]
  161. Dergunov, A.D.; Baserova, V.B. Different Pathways of Cellular Cholesterol Efflux. Cell Biochem. Biophys. 2022, 80, 471–481. [Google Scholar] [CrossRef]
  162. Altesha, M.; Ni, T.; Khan, A.; Liu, K.; Zheng, X. Circular RNA in Cardiovascular Disease. J. Cell Physiol. 2019, 234, 5588–5600. [Google Scholar] [CrossRef]
  163. Zhang, Z.; Yang, T.; Xiao, J. Circular RNAs: Promising Biomarkers for Human Diseases. EBioMedicine 2018, 34, 267–274. [Google Scholar] [CrossRef] [Green Version]
  164. Li, M.; Ding, W.; Liu, G.; Wang, J. Extracellular Circular RNAs Act as Novel First Messengers Mediating Cell Cross-Talk in Ischemic Cardiac Injury and Myocardial Remodeling. J. Cardiovasc. Transl. Res. 2022, 15, 444–455. [Google Scholar] [CrossRef] [PubMed]
  165. Zhao, Z.; Li, X.; Gao, C.; Jian, D.; Hao, P.; Rao, L.; Li, M. Peripheral Blood Circular RNA Hsa_circ_0124644 Can Be Used as a Diagnostic Biomarker of Coronary Artery Disease. Sci. Rep. 2017, 7, 39918. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Wang, L.; Shen, C.; Wang, Y.; Zou, T.; Zhu, H.; Lu, X.; Li, L.; Yang, B.; Chen, J.; Chen, S.; et al. Identification of Circular RNA Hsa_circ_0001879 and Hsa_circ_0004104 as Novel Biomarkers for Coronary Artery Disease. Atherosclerosis 2019, 286, 88–96. [Google Scholar] [CrossRef] [PubMed]
  167. Wu, W.P.; Pan, Y.H.; Cai, M.Y.; Cen, J.M.; Chen, C.; Zheng, L.; Liu, X.; Xiong, X.D. Plasma-Derived Exosomal Circular RNA Hsa_circ_0005540 as a Novel Diagnostic Biomarker for Coronary Artery Disease. Dis. Markers 2020, 2020, 3178642. [Google Scholar] [CrossRef]
  168. Chen, H.H.; Stewart, A.F.R. Transcriptomic Signature of Atherosclerosis in the Peripheral Blood: Fact or Fiction? Curr. Atheroscler. Rep. 2016, 18, 77. [Google Scholar] [CrossRef]
  169. Bazan, H.A.; Hatfield, S.A.; Brug, A.; Brooks, A.J.; Lightell, D.J.; Woods, T.C. Carotid Plaque Rupture Is Accompanied by an Increase in the Ratio of Serum CircR-284 to MiR-221 Levels. Circ. Cardiovasc. Genet. 2017, 10, e001720. [Google Scholar] [CrossRef] [Green Version]
  170. Wang, L.; Xu, G.; Spanos, M.; Li, G.; Lei, Z.; Sluijter, J.P.G.; Xiao, J. Circular RNAs in Cardiovascular Diseases: Regulation and Therapeutic Applications. Research 2023, 6, 38. [Google Scholar] [CrossRef]
  171. Wesselhoeft, R.A.; Kowalski, P.S.; Anderson, D.G. Engineering Circular RNA for Potent and Stable Translation in Eukaryotic Cells. Nat. Commun. 2018, 9, 2629. [Google Scholar] [CrossRef] [Green Version]
  172. Hu, X.; Qin, H.; Yan, Y.; Wu, W.; Gong, S.; Wang, L.; Jiang, R.; Zhao, Q.; Sun, Y.; Wang, Q.; et al. Exosomal Circular RNAs: Biogenesis, Effect, and Application in Cardiovascular Diseases. Front. Cell Dev. Biol. 2022, 10, 948256. [Google Scholar] [CrossRef] [PubMed]
  173. Sadeghi, S.; Tehrani, F.R.; Tahmasebi, S.; Shafiee, A.; Hashemi, S.M. Exosome Engineering in Cell Therapy and Drug Delivery. Inflammopharmacology 2023, 31, 145–169. [Google Scholar] [CrossRef] [PubMed]
  174. Tian, T.; Li, F.; Chen, R.; Wang, Z.; Su, X.; Yang, C. Therapeutic Potential of Exosomes Derived From CircRNA_0002113 Lacking Mesenchymal Stem Cells in Myocardial Infarction. Front. Cell Dev. Biol. 2022, 9, 779524. [Google Scholar] [CrossRef] [PubMed]
  175. Zhou, J.; Qiu, C.; Tang, X.; Wan, R.; Wu, Z.; Zou, D.; Wang, W.; Luo, Y.; Liu, T. Investigation of the Clinicopathological and Prognostic Role of CircMTO1 in Multiple Cancers. Expert. Rev. Mol. Diagn. 2023, 23, 159–170. [Google Scholar] [CrossRef]
  176. Feng, Y.; Yang, Z.; Lv, B.; Xu, X. The Diagnostic and Therapeutic Role of Circular RNA HIPK3 in Human Diseases. Diagnostics 2022, 12, 2469. [Google Scholar] [CrossRef]
  177. Li, G.; Zhu, C.; Qiao, D.; Chen, R. Circ_0001946 Promotes the Development of Acute Myeloid Leukemia by Upregulating PDL1. Turk. J. Haematol. 2023. online ahead of print. [Google Scholar] [CrossRef]
  178. Fu, W.; Wang, X.; Xiang, J.; Chen, S.; Xia, R.; Xie, F.; Chi, B.; Qin, F.; Li, Z.; Mou, L.; et al. CircPTPRA Promotes the Progression of Pancreatic Ductal Adenocarcinoma via the MiR-140-5p/LMNB1 Axis. Cancer Med. 2023, 12, 11651–11671. [Google Scholar] [CrossRef]
  179. Hossain, M.T.; Li, S.; Reza, M.S.; Feng, S.; Zhang, X.; Jin, Z.; Wei, Y.; Peng, Y. Identification of CircRNA Biomarker for Gastric Cancer through Integrated Analysis. Front. Mol. Biosci. 2022, 9, 857320. [Google Scholar] [CrossRef]
  180. Du, W.W.; Zhang, C.; Yang, W.; Yong, T.; Awan, F.M.; Yang, B.B. Identifying and Characterizing CircRNA-Protein Interaction. Theranostics 2017, 7, 4183–4191. [Google Scholar] [CrossRef]
  181. Gao, X.; Xia, X.; Li, F.; Zhang, M.; Zhou, H.; Wu, X.; Zhong, J.; Zhao, Z.; Zhao, K.; Liu, D.; et al. Circular RNA-Encoded Oncogenic E-Cadherin Variant Promotes Glioblastoma Tumorigenicity through Activation of EGFR-STAT3 Signalling. Nat. Cell Biol. 2021, 23, 278–291. [Google Scholar] [CrossRef] [PubMed]
  182. Sinha, T.; Panigrahi, C.; Das, D.; Chandra Panda, A. Circular RNA Translation, a Path to Hidden Proteome. Wiley Interdiscip. Rev. RNA 2022, 13, e1685. [Google Scholar] [CrossRef] [PubMed]
  183. Peng, Y.; Xu, Y.; Zhang, X.; Deng, S.; Yuan, Y.; Luo, X.; Hossain, M.T.; Zhu, X.; Du, K.; Hu, F.; et al. A Novel Protein AXIN1-295aa Encoded by CircAXIN1 Activates the Wnt/β-Catenin Signaling Pathway to Promote Gastric Cancer Progression. Mol. Cancer 2021, 20, 158. [Google Scholar] [CrossRef] [PubMed]
  184. Wen, S.Y.; Qadir, J.; Yang, B.B. Circular RNA Translation: Novel Protein Isoforms and Clinical Significance. Trends Mol. Med. 2022, 28, 405–420. [Google Scholar] [CrossRef]
  185. Li, F.; Tang, H.; Zhao, S.; Gao, X.; Yang, L.; Xu, J. Circ-E-Cad Encodes a Protein That Promotes the Proliferation and Migration of Gastric Cancer via the TGF-β/Smad/C-E-Cad/PI3K/AKT Pathway. Mol. Carcinog. 2023, 62, 360–368. [Google Scholar] [CrossRef]
Cimb 45 00422 g001
Figure 1. Biogenesis and degradation of circRNA. IR—inverted repeats. The green and pink colors indicate their different orientations. RBP—RNA binding protein, U1, U2—small nucleus RNAs, Red and green arrows show an increase and decrease in the amount of U1, U2, and enzyme activity, respectively.
Figure 1. Biogenesis and degradation of circRNA. IR—inverted repeats. The green and pink colors indicate their different orientations. RBP—RNA binding protein, U1, U2—small nucleus RNAs, Red and green arrows show an increase and decrease in the amount of U1, U2, and enzyme activity, respectively.
Cimb 45 00422 g001
Cimb 45 00422 g002
Figure 2. Outline of approaches used to reveal the role of circRNAs in the pathogenesis of CAD.
Figure 2. Outline of approaches used to reveal the role of circRNAs in the pathogenesis of CAD.
Cimb 45 00422 g002
Table 1. List of atherogenesis-related circRNAs, whose expression level is decreased.
Table 1. List of atherogenesis-related circRNAs, whose expression level is decreased.
circRNA
(Host Gene)		Source *Interactions
miRNA/mRNA		Confirmation *Effect,
(Potential Application)		Reference
circ_0026218 (CERS5)HUVECmiR-338-3p/SIRT6Microarray, RT-PCR, DLR, RIPProliferation ↑
Inflammation ↓
Oxidative stress ↓
Apoptosis ↓
(Target for therapy)		[98]
circ_0030042 (FOXO1)HUVECmiR-616-3p/RFX7RT-PCR, DLR,
RIP, RPD		Proliferation ↑
Apoptosis ↓
Inflammation ↓
(Target for therapy)		[99]
circHIPK3
(HIPK3)		Serum, VSMC, HUVECmiR-106a-5p/MFN2RT-PCR, DLROsteogenic and
cartilage differentiation ↓
Vascular calcification ↓
(Target for therapy)		[100]
miR-190b/ATG7[101,102]
circMTO1
(MTO1)		Serum, VSMCmiR-182-5p/RASA1RT-PCR, DLRApoptosis ↑
Proliferation ↓
(Target for therapy)		[103]
circ_0000345
(RSF1)		Serum, ASMCmiR-647/PAPD5RT-PCR,
DLR, RIP		Apoptosis ↑
Proliferation ↓
Inflammation ↓
(Target for therapy)		[84]
Serum, HAEC, HUVECmiR-758/CCND2,
miR-129-5p/TET2		RT-PCR,
DLR, RIP		Proliferation ↑
Apoptosis ↓
(Target for therapy)		[104,105]
circ_06206 (SCRG1)Serum, HUVECmiR-1268b/NR4A1RNA-Seq, RT-PCR, DLRAngiogenesis ↓
(Target for therapy)		[106]
circ_0093887
(Sirt1)		Serum, HAEC, VSMCmiR-758-3p/BAMBI, miR-876-3p/CCND2,
miR-876/SUCNRA,
miR-132/212/SIRT1		RT-PCR,
DLR, RIP, RPD		Proliferation ↑
Apoptosis ↓
Inflammation ↓
(Target for therapy)		[107,108,109]
circ_0001445 (SMARCA5)HUVECmiR-208b-5p/ABCG1RT-PCR, DLR,
RIP, RPD		Proliferation ↑
Inflammation ↓
Foam cells
transformation ↓
(Biomarker,
Target for therapy)		[110]
circSmoc1-2
(Smoc1-2)		VSMCmiR-874-3p/ADAM19RNA-Seq, RT-PCR, Calcium assay, RISHVascular
calcification ↓
(Target for therapy)		[111]
circ_0107197 (TEX14)Serum, VSMCmiR-6509-3p/THAP1RT-PCR,
DLR, RIP		Apoptosis ↑
Proliferation ↓
(Target for therapy)		[112]
circ_0003423 (ZNF532)HUVECmiR-142-3p/SIRT3, SOD2RT-PCR,
DLR, RIP		Proliferation ↑
Oxidative stress ↓
Apoptosis ↓
(Target for therapy)		[113]
* Human Umbilical Vein Endothelial Cell (HUVEC), Vascular Smooth Muscle Cell (VSMC), Aortic Smooth Muscle Cell (ASMC), Human Aortic Endothelial Cell (HAEC), Reverse transcription-polymerase chain reaction (RT-PCR), Dual-luciferase reporter assay (DLR), RNA immune precipitation (RIP), pull-down assay (RPD), High-throughput RNA sequencing (RNA-Seq), RNA in situ hybridization (RISH); ↑: increase; ↓: decrease.
Table 2. List of atherogenesis-related circRNAs, whose expression level is increased.
Table 2. List of atherogenesis-related circRNAs, whose expression level is increased.
circRNA
(Host Gene)		Source *Interactions
miRNA/mRNA		Confirmation *Effect,(Potential Application)Reference
circ_0002984 (ARHGAP32)Serum, VSMCmiR-326-3p/VAMP3,
miR-665/FGF2		RT-PCR, DLR,
RIP, RPD		Inflammation↑
Proliferation ↑
(Target for therapy)		[117,118]
circ_0003645 (C16orf62)HUVECmiR-149-3p/TRAF7RT-PCR,
DLR, RIP		Apoptosis ↑
Proliferation ↓
(Target for therapy)		[119]
circ_0005699 (C16orf62)HUVECmiR-450b-5P/NFKB1RT-PCR, DLRInflammation ↑
(Target for therapy)		[120]
circ_0001946 (CDR1)Serum, mouse ventriclesmiR-7-5p/PARP1RT-PCR, DLR, target prediction in silicoApoptosis ↑
(Target for therapy,
Biomarker)		[121,122]
circ_0026218 (CERS5)Serum, HUVECmiR-188-3p/TLR4RT-PCR, DLR,
RIP, RPD		Apoptosis ↑
Inflammation↑
Oxidative stress ↑
Proliferation ↓
(Target for therapy,
Biomarker)		[123]
circ_0029589 (CHFR)Serum, HUVECmiR-15b-5p/GADD45G,
miR-1197/RAB22A,
miR-370/FOXO1		Microarray, RT-PCR,
DLR, RPD		Apoptosis ↑
Inflammation ↑
Oxidative stress ↑
proliferation ↓
(Target for therapy)		[124,125,126]
circ_0003575 (CHMP5)HUVECmiR-532-5p/ROCK2RT-PCR,
DLR, RIP		Apoptosis ↑
Inflammation ↑
Proliferation ↓
(Target for therapy)		[127]
circCOL1A1
(COL1A1)		Serum, VSMCmiR-30a-5p/SMAD1RT-PCR, RISH, DLR, RPD VSMC transformation ↑
(Target for therapy,
Biomarker)		[128]
circ_0050486 (GPI)THP-1miR-1270, miR-145/NF1A, MMP16, USP31RT-PCR, DLRInflammation ↑
Apoptosis ↑
(Target for therapy)		[129]
Serum, HAECmiR-182-5p/MYD88RT-PCR,
DLR, RIP		Proliferation ↓
(Target for therapy,
Biomarker)		[130]
circ_0044073 (GRN)Serum, HUVEC, HUVSMCmiR-107/JAK1RT-PCR,
DLR, RPD		Proliferation ↑
(Target for therapy)		[92]
circ_0057583 (HECW2)Serum, CMECmiR-942-5p/TLR4RT-PCR,
DLR, RPD		Apoptosis ↑
Proliferation ↓
(Target for therapy)		[31]
circ_0091822 (IRAK1)Serum, HUVECmiR-330-5p/TRIM14,
miR-661/RAB22A		RT-PCR,
DLR, RIP, RPD		Inflammation ↑
Apoptosis ↑
Oxidative stress ↑
Proliferation ↓
(Biomarker,
Target for therapy,)		[131,132]
circ_0018146 (ITGB1)SerummiR-342-3p/NFAM1Microarray, RT-PCR,
DLR, RPD		Dendritic
cell maturation ↓
(Target for therapy,
Biomarker)		[133]
circ_0001879 (NIPSNAP3A)Serum
HUVEC		miR-6873-5p/HDAC9RT-PCR,
DLR, RIP		Inflammation ↑
Proliferation ↓
Cholesterol transport ↓
(Target for therapy)		[134]
circ_0009135 (NPHP4)Serum
Monocytes,
EVs		miR-1231/EGFRMicroarray, RT-PCR,
DLR, RIP, RPD		Heterogeneous
adhesion ↑
(Target for therapy,
Biomarker)		[135]
circ_0033596 (PACS2)HUVECmiR-217-5p/CLIC4RT-PCR,
DLR, RIP		Apoptosis ↑
Proliferation ↓
(Target for therapy)		[136]
circ_0008896 (PPAPDC1A)VSMCmiR-633/CDC20BRT-PCR,
DLR, RIP		Proliferation ↑
(Target for therapy)		[137]
circPTPRA
(PTPRA)		Serum, VSMCmiR-636/SP1RT-PCR, DLRProliferation ↑
Apoptosis ↓
(Target for therapy,
Biomarker)		[138]
circ_0002194 (RELL1)HUVECmiR-637/PACS2,
miR-6873-3p/MYD88		Microarray, RT-PCR,
DLR, RIP,		Apoptosis ↑
Proliferation ↓
Inflammation ↑
Oxidative stress ↑
(Target for therapy)		[139,140]
circ_0124644 (ROBO2)Serum, HASMCmiR-149/TRAF6Microarray, RT-PCR,
DLR, RPD		Proliferation ↑
Inflammation ↑
Apoptosis ↓
(Biomarker) 		[141]
HUVEC,
Serum, CMEC		miR-370-3p/FOXO4,
miR-186-5p/TRIM14		RT-PCR, DLR,
RIP, RPD		Inflammation ↑
Apoptosis ↑
Proliferation ↓
(Biomarker,
Target for therapy)		[142,143]
circ_0001292 (SCAP)Serum, THP-1miR-221-5p/PDE3BRT-PCR,
DLR, RPD		Inflammation ↑
Oxidative stress ↑
Lipid accumulation ↑
(Biomarker)		[144]
circ_102541
(SIPA1L1)		Serum, HUVECmiR-296-5p/PLK1RT-PCR,
DLR		Proliferation ↑
Apoptosis ↓
(Target for therapy,
Biomarker)		[145]
circ_0004104 (SPARC)Serum, HUVECmiR-942-5p/ROCK2RT-PCR, DLR,
RIP, RPD		Inflammation ↑
Apoptosis ↑
Proliferation ↓
(Target for therapy,
Biomarker)		[146]
circ_0007478 (TM7SF3)Serum, VSMCmiR-638/ROCK2RT-PCR,
DLR, RIP		Proliferation ↑
(Target for therapy
Biomarker)		[147,148]
THP-1miR-765/EFNA3Microarray, RT-PCR, DLRFoam cells
transformation ↑
(Target for therapy,
Biomarker)
circ_0021155 (TMEM41B)VSMCmiR-4459/TRPM7RNA-Seq,
RISH,
RT-PCR, DLR		Proliferation ↑
VSMC transformation ↑
(Target for therapy)		[149]
circ_0072951 (TNPO1)Serum, VSMCmiR-181b/NOTCH1RT-PCR, DLRProliferation ↑
(Target for therapy,
Biomarker)		[150]
circ_0010283 (UBR4)Serum, VSMCmiR-107/ROCK,
miR-370–3p/HMGB1, miR-133a-3p/PAPPA 		RT-PCR, DLR,
RIP, RPD		Proliferation ↑
(Target for therapy,
Biomarker)		[151,152,153]
circ_0086296 (UHRF2)Carotid plaque, HUVEC, aorta of atherosclerotic micemiR-576-3p/IFIT1,
STAT1		Microarray, RT-PCR, RISH, Sanger-Seq, DLR, RIP, RPDInflammation ↑
Lipid accumulation ↑
(Target for therapy)		[154]
circ_0003204 (USP36)Serum, VSMCmiR-182-5p/KLF5,
miR-942-5p/HDAC9 		RT-PCR, DLR, RPD, RIPProliferation ↑
(Target for therapy,
Biomarker)		[155,156]
circ_0090231 (USP9X)Serum, HUVECmiR-9-5p/TXNIP,
miR-599/CLIC4 		RT-PCR,
DLR, RIP		Apoptosis ↑
Oxidative stress ↑
Inflammation ↑
Proliferation ↓
(Target for therapy,
Biomarker)		[157,158]
circ_0006896 (VIRMA)EVs,
HUVEC		miR-1264/DNMT1Microarray, RISH, RT-PCR, DLRPlaque formation ↑
Proliferation ↑
(Target for therapy,
Biomarker)		[159]
* Vascular Smooth Muscle Cell (VSMC), Human Umbilical Vein Endothelial Cell (HUVEC), Human leukemia monocytic cell line (THP-1), Human Aortic Endothelial Cell (HAEC), Human Umbilical Vein Smooth Muscle Cell (HUVSMC), Cardiac Microvascular Endothelial Cell (CMEC), Human Aortic Smooth Muscle Cell (HASMC), Extracellular vesicles (EVs), Reverse transcription-polymerase chain reaction (RT-PCR), Dual-luciferase reporter assay (DLR), RNA immune precipitation (RIP), pull-down assay (RPD), High-throughput RNA sequencing (RNA-Seq), RNA in situ hybridization (RISH); ↑: increase; ↓: decrease.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Dergunova, L.V.; Vinogradina, M.A.; Filippenkov, I.B.; Limborska, S.A.; Dergunov, A.D. Circular RNAs Variously Participate in Coronary Atherogenesis. Curr. Issues Mol. Biol. 2023, 45, 6682-6700. https://doi.org/10.3390/cimb45080422

AMA Style

Dergunova LV, Vinogradina MA, Filippenkov IB, Limborska SA, Dergunov AD. Circular RNAs Variously Participate in Coronary Atherogenesis. Current Issues in Molecular Biology. 2023; 45(8):6682-6700. https://doi.org/10.3390/cimb45080422

Chicago/Turabian Style

Dergunova, Liudmila V., Margarita A. Vinogradina, Ivan B. Filippenkov, Svetlana A. Limborska, and Alexander D. Dergunov. 2023. "Circular RNAs Variously Participate in Coronary Atherogenesis" Current Issues in Molecular Biology 45, no. 8: 6682-6700. https://doi.org/10.3390/cimb45080422

Article Metrics

Back to TopTop