v
Search
Advanced Search

Publications > Journals > Gene Expression > Article Full Text

  • Review Article
  • OPEN ACCESS

Non-coding RNA and Atherosclerosis

  • Aram Adyan1,* ,
  • Evgeny Bezsonov1,2,3,4,5,* ,
  • Eugene Grebenshchikov1,
  • Alexandr Grinev1 and
  • Denis Bogomolov1
 Author information  Cite
Gene Expression   2024;23(1):57-68

doi: 10.14218/GE.2023.00117

Abstract

The overwhelming majority of genes in the human genome encode RNA molecules that are not translated into proteins. These RNA molecules are named non-coding RNAs (ncRNAs). ncRNAs play a crucial role in the regulation of gene expression and abnormalities in ncRNAs can cause disease progression, including atherosclerosis. ncRNAs regulate different stages of atherosclerosis progression, such as foam cell formation and lipid metabolism. Diverse types of ncRNAs have been studied, but the best known and widely used are small non-coding (sncRNAs), specifically microRNAs and small interfering RNAs, which are ∼22 nucleotides long. The majority of drugs based on ncRNAs are composed of sncRNAs. There is strong evidence that besides sncRNAs, other types of ncRNAs, such as long ncRNAs and circular RNAs, take part in the regulation of gene expression. This review summarized recent advances in ncRNAs and atherosclerosis.

Keywords

Non-coding RNA, Atherosclerosis, Drugs, Inflammation, Epithelial-mesenchymal transition

Introduction

The end product of a gene can be either a protein or an RNA molecule. These RNAs are called non-coding RNAs (ncRNAs). They can be divided into housekeeping ncRNAs, which include ribosomal RNA, transfer RNA, small nuclear RNA, small nucleolar RNA and regulatory ncRNA.1 Regulatory ncRNAs can be classified into small ncRNAs (sncRNAs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs); some authors refer to circRNAs as lncRNAs, while others classify them into distinct groups.1,2

The main groups of sncRNAs are microRNAs (miRNAs) and small interfering RNAs (siRNAs). miRNAs are generally 22 nucleotides long which participate in gene expression regulation. Their action is based on interactions with messenger RNA (mRNA) mediated by base pairing between the miRNA and complementary sequences in the target mRNA. There are three different miRNA effects on mRNA: cleavage of mRNA, translation repression or/and removal of the polyA tail and cap from mRNA ends.3,4

The first ever investigated miRNA was lin-4 from Caenorhabditis elegans. Lin-4 is responsible for the regulation of larval development timing in round worms.3,5 Its mechanism of action is based on translation repression of the lin-14 gene, whose protein product is involved in controlling the timing of developmental events during the larval stages. Lin-4 promotes the transition from the first larval stage to the second larval stage and represses the later developmental stages. The lin-4 miRNA interacts with complementary sites in the lin-14 mRNA and acts as a negative regulator.6

siRNAs are also similar to miRNAs; however, there are several key differences between them. siRNAs are typically derived from exogenous sources, such as viral or synthetic double-stranded RNA invading cells. In contrast, miRNAs are endogenously produced within cells from distinct genes that encode stem-loop RNA precursors. The RNase III endonuclease Dicer participates in their maturation. siRNAs typically exhibit perfect or near-perfect complementarity to their target mRNAs. This allows for highly specific gene silencing through mRNA degradation. miRNAs usually have partial complementarity to their target mRNAs and silence genes through translational repression rather than mRNA cleavage. Furthermore, siRNAs regulate only the specific gene that expresses them, while miRNAs can regulate different genes.3,7

LncRNAs are defined as ncRNAs longer than 200 nucleotides. They can regulate gene expression through diverse mechanisms. Generally, lncRNAs are transcribed by RNA Polymerase II. Most of these RNAs undergo post-transcriptional modifications, such as capping and polyadenylation of their ends, similar to mRNAs, which are essential for stability.8 LncRNAs can be localized in different cellular compartments, including the nucleus, cytoplasm, and even extracellular space, but a large percentage of them are localized in the nucleus.9 There are several mechanisms of lncRNA-mediated gene expression regulation. Due to the ability to identify complementary sequences, some lncRNAs can bind to specific DNA sequences and recruit chromatin-modifying complexes, such as histone methyltransferases, acetylases, and deacetylases or DNA methyltransferases, to regulate the epigenetic state of target genes.10 This can lead to changes in chromatin structure and gene expression. Another mechanism involves interactions with RNA molecules, such as mRNAs, which regulate post-transcriptional processes, or with miRNAs, functioning as miRNA sponges.8,11 According to their mechanisms of action, lncRNAs can be classified as cis-acting, which act at the site of transcription and affect the expression of neighboring genes, or trans-acting, which function beyond the site of synthesis.12 For example, trans-acting lncRNAs can function by recruiting chromatin-modifying complexes to regulate distant genes or act as miRNA sponges.13 The main types of ncRNAs and their potential sites of action are shown in Figure 1.

Types of ncRNAs and their places of action.
Fig. 1  Types of ncRNAs and their places of action.

circRNA, circular RNA; dsRNA, double-stranded RNA; lncRNA, long non-coding RNA; mRNA, messenger RNA; miRNA, microRNA; ncRNA, non-coding RNA; pre-miRNA, precursor miRNA; pri-miRNA, primary miRNA; RISC, RNA-induced silencing complex; siRNA, small interfering RNA.

ncRNAs in lipid metabolism

The most studied miRNA involved in the regulation of cholesterol homeostasis is miR-33, which has two isoforms in humans: miR-33a and miR-33b. These miRNAs are encoded within sterol regulatory element-binding protein (SREBP) genes. SREBPs belong to a family of transcription factors that regulate the expression of genes involved in the synthesis of various lipids. Specifically, miR-33a is encoded in the intron of SREBP2, and miR33b is encoded in the intron of SREBP1.14 SREBP1 mainly activates genes involved in fatty acid synthesis, and SREBP2 mainly activates cholesterol synthesis.15 Excess cholesterol is removed from cells by the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, and cholesterol is subsequently captured by high-density lipoprotein.16 It has been revealed that the mRNAs of ABCA1, ABCG1 and NPC1 genes, which are involved in the intracellular trafficking of cholesterol, are targets of miR-33. miR-33 inhibits the expression of these proteins and thus reduces cholesterol efflux.14,17,18

Additionally, there are other miRNAs that target ABCA1. miR-148a binds to ABCA1 mRNA and inhibits its expression. In vivo experiments have demonstrated that the downregulation of miR-148a increases the level of cholesterol in high-density lipoprotein. miR-148a also regulates the level of low-density lipoproteins (LDLs) by targeting the mRNA of the LDL receptor. Downregulation of LDL receptor expression leads to a decrease in LDL uptake by hepatic cells and thus an increase in circulating LDL cholesterol levels, which is a risk factor for atherosclerosis.19 miR-26 and miR-758 directly target ABCA1.20,21

lncRNAs also participate in the regulation of lipid metabolism. For example, the lncRNA MeXis interacts with the protein DDX17 and facilitates its action. DDX17 enhances the liver X receptor-mediated expression of ABCA1. This protein is a nuclear receptor that stimulates cholesterol efflux in response to high cholesterol levels in cells.22 The lncRNA uc.372 upregulates the expression of genes involved in fatty acid synthesis and uptake, such as ACC, SCD1, and CD36, which leads to lipid accumulation. This effect is caused by preventing the maturation of miR-195 and miR-4688 via uc.372. Downregulation of miR-195 and miR-4688 occurs due to the ability of uc.372 to bind with the primary miRNAs pri-miR-195 and pri-miR-4668.23

The role of ncRNAs in inflammation

Activation of inflammation is an important biological phenomenon in various diseases. ncRNAs are activated in inflammatory diseases, either by directly affecting components of inflammatory sites or by controlling the activity of various factors that control inflammatory activation.24

ncRNAs are critical in regulating the expression of genes associated with certain types of cells that cause inflammation. For example, miRNAs, such as miR-126, miR-132, miR-146, miR-155 and miR-221, are important transcriptional regulators of several mediators associated with inflammation,25 and several lncRNAs, such as long noncoding inflammation-associated RNAs, play critical roles in inflammation—regulation of cytokines and inflammasome activation.26 Knockdown of hLinfRNA1 has been shown to suppress the lipopolysaccharide-induced expression of cytokines and pro-inflammatory genes, such as interleukin (IL) 6, IL1β and tumor necrosis factor (TNF) α.26

The role of ncRNAs in vascular cell proliferation

Different ncRNAs may play different roles within the life cycle of vascular smooth muscle cells (SMCs). For instance, the overexpression of miR-130a,27 miR-146a,28 and the lncRNA RNCR3 promote SMC proliferation,29 and miR-34a regulates proliferation and migration.30 A number of studies have demonstrated a correlation between the development of atherosclerotic changes in blood vessels and the concentration of certain ncRNAs, but the underlying mechanism has not been fully elucidated.

In 2016, smooth muscle-enriched lncRNA was experimentally demonstrated as one of the drivers of vascular SMC proliferation.31 One of the proposed mechanisms of this phenomenon is the interaction with the promoter region of the hyaluronidase 2 gene, which is a marker of atherosclerosis progression.32 Another ncRNA, lncRNA hoxa cluster antisense RNA 3, affects the transcriptional processes by regulating histone H3K9 acetylation, leading to an increase in the number of pulmonary artery SMCs in the S+G2/M phase. Knockdown of this ncRNA leads to the opposite effect—a decrease in the number of pulmonary artery SMCs in the S+G2/M phase.33

On the other hand, the reverse effect of ncRNAs in the SMC life cycle is also reported. It was demonstrated that snRNA-p21 can act as an enhancer to enhance the expression of the p53 gene, which allows p53 to interact with the p300 protein, ultimately leading to the inhibition of SMC proliferation and apoptosis.34

The role of ncRNAs in vascular cell adhesion and migration

miR-92a increases the expression of endothelial adhesion molecules and the adhesion of leukocytes to the endothelium through targeting Kruppel-like factor 2 (KLF2) and KLF4.35 miR-126 is expressed at high levels in endothelial cells compared to other miRNAs, and it binds to the 3′ untranslated region of vascular cell adhesion molecule 1 mRNA, leading to inhibition of its translation. This inhibition blocks the adhesion of leukocytes to vascular walls, thereby preventing their infiltration.36 Blocking miR-126 with antisense RNA leads to an increase in vascular cell adhesion molecule 1 expression induced by TNF-α.36 miRNA-17-3p, miRNA-141, miR-221, and miR-222 reduce the adhesion of leukocytes to endothelial cells by acting on the common target intercellular adhesion molecule-1.37–39 miR-31 inhibits leukocyte adhesion (and rolling) on the endothelium by acting on E-selectin.40 miR-146a/b inhibits the expression of endothelial adhesion molecules by targeting IRAK1, TRAF6.41 miR-100 was found to suppress the expression of endothelial adhesion molecules via the attenuation of NF-kB signaling, leading to decreased interaction between leukocytes and the endothelium.42

Role of ncRNAs in angiogenesis

The role of ncRNAs in angiogenesis has been studied mostly in cancer research. miR-21 is upregulated in tumors and has different targets: PTEN (which leads to the induction of angiogenesis by enhancing the expression of vascular endothelial growth factor (VEGF) and HIF-1),43 STAT3 (which leads to a decrease in VEGF levels via the knockout of STAT3),44 and THBS1 (which leads to the inhibition of THBS1 expression in endothelial cells).45 miR-126 is mostly downregulated in tumors, and it also has several targets related to its mostly anti-angiogenic activity: VEGF, VEGFA, LRP6 and PIK3R2.46–49 miR-93 is upregulated in tumors because it has pro-angiogenic activity by targeting VEGF, EPLIN, LATS2, and IL8.50–53 LncRNAs also involved in angiogenesis, with H19, HOTAIR and MVIH ncRNA being upregulated in tumors with VEGF and some specific targets for each ncRNA mentioned.54–59 The lncRNA MANTIS has been shown to affect endothelial angiogenic function via action on BRG-1.60 CircRNAs (circ-ATXN1, circ-SHKBP1, hsa-circ-0000515, circ-0056618, circ-PRRC2A, circRNA-MYLK, and circ-DICER1), which are upregulated in tumors, can also influence angiogenesis via different targets (MMP2, VEGFA, VEGF, CXCL10, CXCR4, TRPM3, and PI3K/AKT).61–67

Atherosclerosis-what is it? The basis of pathological changes occurring in atherosclerosis

Atherosclerosis is a chronic inflammatory vascular disease characterized by the formation of plaques within the intima of large- and medium-sized arteries. Multiple experimental and clinical data, including studies with animal models and humans, suggest that this disease is related to the disturbance of lipid metabolism.68 Abnormal lipid accumulation, which causes the formation of plaques, leads to damage to the intima, inflammation and fibrosis.69 The mouse model is the most commonly used animal model for studying atherosclerosis.70 Mice exhibit innate resistance to atherosclerosis due to the absence of cholesteryl ester transfer protein, which contributes to the exchange of cholesteryl ester and triglycerides between different lipoproteins.71 However, knockout of specific genes involved in lipid metabolism, such as the apolipoprotein E (ApoE) gene or LDL receptor,72,73 leads to the development of atherosclerosis-like changes in these mice.

Over time, atherosclerosis can cause narrowing of the arteries, which can restrict blood flow and potentially lead to severe complications, such as myocardial infarction and cerebrovascular disease, leading to stroke and other complications.

Plaques are multicomponent structures that include lipids, cholesterol, calcium, connective-tissue elements, cells and their remains. Plaque development can be divided into several stages. Initially, isolated macrophages transform into foam cells. As the number of foam cells increases, intracellular lipid accumulation starts, which subsequently results in the formation of a lipid core. As the plaque progresses, SMCs migrate from the arterial wall to the developing plaque. These SMCs produce collagen and other extracellular matrix proteins, contributing to the formation of the fibrous cap. The fibrous cap provides structural support to protect the plaque. Sometimes different parts of plaques are mineralized by calcium, which makes the structure harder.74,75

LDLs (another important player in atherosclerosis development) transport cholesterol from the liver to cells. Modified LDLs, such as desialylated and oxidized ones, initiate excessive lipid accumulation in artery walls and trigger an inflammatory response in the artery. Modified LDLs trigger endothelial cells to synthesize leukocyte adhesion molecules,76–78 such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1.79,80 This leads to the recruitment of immune cells, such as monocytes, to the intima, representing one of the earliest events in atherosclerosis development.81 Monocytes then differentiate into macrophages that engulf the modified LDLs via scavenger receptors. Excessive lipid uptake leads to lipid droplets accumulation in macrophages, which are subsequently transformed into foam cells, contributing to the formation of the lipid core within the plaque.82

The main source of foam cells is macrophages, although a small portion of these cells may originate from endothelial and vascular SMCs.83 The process by which epithelial cells transform into mesenchymal cells is called epithelial-mesenchymal transition (EMT). EMT plays a crucial role in early embryonic development, contributing to the formation of germ layers: ectoderm, mesoderm, and endoderm.84 During EMT, epithelial cells lose their features such as cell polarity and cell-cell adhesion and acquire mesenchymal characteristics, allowing them to migrate and invade surrounding tissues.85 EMT occurs not only during embryonic development but also in adulthood, contributing to processes such as tissue regeneration and the development of different diseases.86 The EMT subcategory in which endothelial cells undergo this transition is called endothelial-mesenchymal transition (EndMT). Studies have shown that, besides atherosclerosis, cardiac fibrosis is also linked with EndMT.87 Research indicates a correlation between the severity of coronary atherosclerosis and decreased endothelial expression of FGF receptor 1, endothelial activation of TGF-β signaling, and the degree of EndMT.88 It has been found that histone deacetylases (HDACs), particularly HDAC9, play an important role in EndMT upon atherosclerosis development, and knock-out endothelial cell-specific HDAC9 leads to reduced plaque size and increased plaque stability in atherosclerosis-prone mice.89

More attention gets attracted to the role of immune cells other than macrophages (for example, T- and B-cells) in the development and progression of atherosclerosis.90 Atherosclerotic plaques contain significantly high amounts of CD4+ T cells.91 B cells can regulate atherosclerosis development by producing cytokines and antibodies.92 It has been found that the quantity of the chemokine receptor CXCR4 residing on human CD20+CD27+CD43+ B1 cells is associated with the level of circulating IgM antibodies recognizing MDA-LDL, and the higher expression of CXCR4 in B1 cells corresponds to reduce coronary artery plaque burden in patients.93

Mitochondrial dysfunction could well be one of the pathological factors contributing to atherosclerosis development.94,95 Certain mutations of mitochondrial DNA (mtDNA) in white blood cells of patients were shown to be associated with cardiac angina (G14459A and C5178A), with carotid atherosclerosis or the presence of coronary heart disease (C3256T, T3336C, G12315A, G13513A, G14459A, G14846A, and G15059A).96,97 Additionally, atherosclerotic lesions in the human aorta contain mtDNA mutations like A1555G, C3256T, T3336C, G13513A, and G15059A.98 The accumulation of mtDNA mutations may lead to mitochondrial dysfunction, increased reactive oxygen species (ROS) production, oxidative stress and pro-inflammatory cytokine release.99 Mitochondrial damage-associated molecular patterns can trigger sterile inflammation via different signaling pathways, including NF-kB, Toll-like receptors, and NLRP3,100 and damaged mtDNA itself may serve as a damage-associated molecular pattern, causing an inflammatory response.101

Interestingly, mitochondrial DNA mutations and mitochondrial dysfunction are associated with other diseases, including neurological disorders,102 diabetes,103 muscle atrophy and non-alcoholic fatty liver disease.104–106

Atherosclerosis can also be considered an autoimmune disease; thus, certain approaches related to the treatment of such diseases can potentially be applied.107,108 The autoimmune nature of atherosclerosis can be demonstrated by the presence of autoantibodies against oxidized LDL (oxLDL), β2 glycoprotein I and heat shock proteins.109 oxLDL binds to β2 glycoprotein I to form a complex capable of triggering autoimmune reactions.110 The binding of C-reactive protein to ox-LDL, enhances its interaction with Fcγ receptors in macrophages, which may augment oxLDL uptake by macrophages (a process not observed with native LDL).111

Atherosclerosis and amyloid-related diseases are closely associated with aging. Opinions about the possible interconnection between these two different pathologies have appeared relatively recently.112 For example, deposits of Apo-AI-based amyloid were found in the intima and atherosclerotic plaques of carotid artery specimens from a significant portion of atherosclerotic patients.113 The number of stenoses was higher in Alzheimer’s disease patients than in the control population, as well as the number and degree of atherosclerosis in certain cerebral arteries.114 There is a certain connection between vascular amyloidosis and the following factors, some of which can also be associated with atherosclerosis: MMP-2/9, Ang II, Medin, MFG-E8, and MCP-1.112 However, the exact mechanism underlying the connection between atherosclerotic changes and amyloid deposition has yet to be determined. One could hypothesize that amyloid deposition further exacerbates chronic inflammation in the vessel wall since, for example, systemic amyloidosis can be associated with chronic inflammation.115

This hits at potential benefits (for the prevention or reduction of severity of atherosclerosis development) through early diagnosis and treatment of amyloid-related diseases.116 Thus, the development of new approaches to target amyloid-caused diseases holds significant importance, and yeast could serve as an important model organism for new insights for the development of such therapies (for example, based on findings about yeast anti-prion/amyloid/aggregate systems or about amyloid properties in general).117,118 The main pathological factors contributing to atherosclerosis development are shown in Figure 2.

Main pathological factors contributing to atherosclerosis development.
Fig. 2  Main pathological factors contributing to atherosclerosis development.

LDL, low-density lipoprotein.

Initial stages of atherosclerosis development

Understanding the main pathological factors contributing to atherosclerosis development allows us to guess the sequence of events during the initial stages of atherosclerosis development.119 Pre-atherosclerotic lesions in humans are believed to be diffuse thickening of the artery intima in atherosclerosis-prone areas of arteries where there is disturbed blood flow even at a very early age.120 Vascular SMCs migrate from the media into the intima, leading to the production of a negatively charged extracellular matrix that can bind to positively charged ApoB-based lipoproteins.121 This leads to the retention of lipids in the subendothelial space following endothelial dysfunction and activation of endothelial cells, resulting in the production of pro-inflammatory cytokines and adhesion molecules, and increased permeability of the endothelium.122 Accumulated lipids in the intima can be further modified (for example, oxidized), activating the innate immune response.123 Monocytes from the circulation are attracted to initial atherosclerotic lesions and reach the intima, where they differentiate into macrophages. These macrophages accumulate lipids and change into foam cells, accumulating in the intima.124 During the abovementioned processes, the migration (and proliferation) of vascular SMCs into the intima continues, and the production of collagen by these cells eventually leads to the formation of a fibrous cap.125

ncRNAs can affect atherosclerosis development at different stages. For example, the expression of miR-155-5p in the case of early atherosclerosis restricts lesion formation by reducing the proliferation of macrophages, but the formation of advanced lesions is increased by miR-155-5p by impairing efferocytosis induced by inflammation.126

The connection of atherosclerosis and cardiovascular diseases with ncRNAs

ncRNAs take part in the regulation of gene expression and can act not only inside the cell where they were synthesized but also outside it. Generally, donor cells can secrete ncRNAs into the extracellular space through extracellular vesicles, which reach the recipient cell and regulate internal processes. Secretion of ncRNAs can occur in various ways. Extracellular vesicles are not a name for one type of vesicles; this term includes three different types of vesicles: exosomes, microvesicles (MVs) and apoptotic bodies. This classification is based on the way those vesicles were generated.127

Exosomes originate from the multivesicular body (MVB), which is a component of the endosomal-lysosomal system, and fuse with the cell membrane. The MVB contains vesicles up to 100 nm in diameter. These vesicles are termed intraluminal vesicles.128 Upon fusion with the membrane, the MVB releases these intraluminal vesicles in the extracellular space, known as exosomes.129

MVs (40–1,000 nm in diameter), which are also called ectosomes, microparticles or shedding vesicles, are formed through outward budding of the cell membrane mediated by actin and myosin interactions.130

Apoptotic bodies, also known as apoptotic vesicles, are released from cells undergoing programmed cell death (apoptosis) and contain cellular components, including organelles, proteins and nucleic acids. They have a larger size than exosomes and MVs, ranging from 50 nm up to 5,000 nm in diameter.127

ncRNAs are secreted inside the cell through various ways, including exosomes, MVs, and apoptotic bodies, and can also be components of lipoproteins or ribonucleoproteins.131

ncRNAs are involved in various cellular processes, including gene expression regulation and cell communication. In various cardiovascular diseases (CVDs), alterations in ncRNA levels occur. For example, it was demonstrated that miRNAs are necessary for cardiovascular system development.132 In this study, mice with cardiac-specific knockout of the Dicer gene, crucial for miRNA maturation showed decreased mature miRNA levels, causing changes in gene expression in the heart, particularly in genes that are involved in regulating the structure and function of heart muscle cells. These changes ultimately led to the development of dilated cardiomyopathy and heart failure, causing the death of the mutant mice.132

Alterations in the quantities of different miRNAs have been revealed during CVD. For example, the expression of miR-126 is significantly lower in patients with coronary artery disease than in healthy individuals.133 Another study revealed that miR-122 and miR-370 levels are greater in patients with high levels of lipids in the blood and that high levels of these miRNAs are associated with a high risk of coronary artery disease.134

The first report on the association of miRNAs with CVD was published in 2006. This study demonstrated correlations between miRNA expression patterns and heart failure and cardiac hypertrophy in mice and humans. Numerous studies describing alterations in miRNA levels during CVD have been published.135

Quantitative changes during various CVD types have also been observed in lncRNAs and circRNAs.136

Why can we use ncRNAs as biomarkers? ncRNAs can exhibit tissue-specific or cell-specific expression patterns; thus, they can act as indicators of specific pathological processes. These molecules can be detected in bodily fluids, and their levels can be measured.136

The first description of morphological changes in CVD was provided by van Rooij et al. They reported that the overexpression of specific miRNAs, such as miR-195 and miR-199a, resulted in changes in the phenotypes of myocytes.135 In endothelial cells, the expression of several miRNAs depends on hemodynamic conditions, specifically the shear stress exerted by blood flow on the endothelial surface. These miRNAs, also called flow-sensitive miRNAs, are termed mechano-miRNAs.137 For example, the mechano-miRNA miR-92a affects inflammatory signaling pathways. Overexpression of miR-92a led to a significant decrease in KLF4 and KLF2. Conversely, inhibition of miR-92a increases the levels of KLF4 and KLF2, both possessing anti-inflammatory properties.138 Research in mice with deficient miR-92a showed a significant decrease in macrophage and T lymphocyte accumulation, leading to reduced inflammatory responses.138,139

Interestingly, ncRNAs are significantly involved in the control of T-cell function. For example, deletion of the components involved in the processing of miRNAs (DGCR8, Drosha, and Dicer) leads to a decrease in the proliferation of T cells.140–142 Additionally, CD4+ T cells with miRNA deficiency exhibit increased Th1 differentiation and cytokine production after activation.143 lncRNAs, such as IFNG-AS1, which is specific for Th1 cells, can be associated with a certain stage of T cells.144

In macrophages, miR-155 increases during atherosclerosis and promotes inflammation. In a study with two mouse groups: apolipoprotein E-deficient (ApoE−/−) and ApoE−/− combined with miR-155 deficient (miR155−/−), findings showed that ApoE−/− mice deficient in miR-155 exhibited reduced macrophage inflammation compared to those with normal miR-155 levels.145

The list of ncRNAs potentially involved in atherosclerosis pathogenesis is shown in Table 1.14,19-23,27-29,145-148

Table 1

ncRNAs associated with atherosclerosis

ncRNATargetsEffectsReference
miR-33a, miR-33bABCA1, ABCG1, NPC1Reduces efflux of cholesterol from cell14
miR-148aABCA1Reduces efflux of cholesterol from cell, increases the level of LDL19
miR-26ABCA1Reduces efflux of cholesterol from cell20
miR-758ABCA1Reduces efflux of cholesterol from cell21
MeXisDDX17Promotes enhancement of ABCA1 expression22
uc.372pri-miR-195, pri-miR-4668Increases lipid accumulation23
miR-130aMEOX2Stimulates SMC proliferation27
miR-146aKLF4Stimulates SMC proliferation28
miR-155SOCS1Promotes inflammation145
miR-195CDC42, CCND1, FGF1Inhibits SMC proliferation, migration146
miR-199a-5pVEGFA, NOS3Represses vascularization, represses nitric oxide synthesis147
RNCR3miR-185-5pPrevents inflammation29
H19miR-199a-5p, PKD1, miR-29a, miR-29cPromotes proliferation, inhibits apoptosis, stimulates vascularization148

ABC, ATP-binding cassette; ABCA1, ABC subfamily A member 1; ABCG1, ABC subfamily G member 1; CCND1, cyclin D1; CDC42, cell division cycle 42; DDX17, DEAD-box helicase 17; FGF1, fibroblast growth factor 1; KLF4, Kruppel-like factor 4; LDL, low-density lipoprotein; MEOX2, mesenchyme homeobox 2; MeXis, macrophage-expressed LXR-induced sequence; miRNA, microRNA; ncRNA, non-coding RNA; NPC1, Niemann-Pick type C1; NOS3, nitric oxide synthase 3; PKD1, polycystic kidney disease 1; pri-miRNA, primary miRNA; RNCR3, retinal non-coding RNA3; SMC, smooth muscle cell; SOCS1, suppressor of cytokine signaling 1; VEGFA, vascular endothelial growth factor A.

Therapy with ncRNAs

Therapeutic approaches involving ncRNA include the use of RNA interference effectors, such as siRNAs or miRNAs, as well as DNA short antisense oligonucleotides (ASOs) or miRNA sponges.

An advantage of ncRNAs-based drugs is that they can target various locations, unlike protein-based drugs, whose targets are mainly extracellular proteins.149

In contrast to miRNAs, which can silence many genes because they do not require full complementary interactions, siRNA mechanism of action is based on full complementarity with the target mRNA; hence siRNA affects the expression of a single gene.

The first clinically approved siRNA, patisiran in 2018, targeted transthyretin mRNA for hereditary transthyretin amyloidosis.150

Another siRNA-based drug, Oplasiran developed by Amgen, has shown promise in decreasing lipoprotein (a) levels by preventing translation of the apo(a) protein. Additionally, Oplasiran has demonstrated reductions in LDL cholesterol and apolipoprotein B levels, though the underlying mechanisms warrant further clinical exploration.151

Another siRNA drug is inclisiran (brand name Leqvio). It was approved for use in the EU in 2020 and in the USA in 2021.152 Inclisiran decreases the serum levels of LDL by silencing PCSK9 mRNA in the liver. PCSK9 facilitates the degradation of LDL receptors; by reducing PCSK9 levels, the uptake of LDL by hepatocytes increases, consequently lowering the serum levels of LDL.153,154

ASOs are oligonucleotides that are complementary to specific RNAs including mRNAs, miRNAs, etc. ASOs were initially single-stranded DNA, termed antisense oligodeoxynucleotides.155,156 Modern ASOs generally comprise DNA nucleotides and modified nucleotide regions. To protect these oligonucleotides from cellular nucleases and improve their efficacy, they are chemically modified. All three parts of the nucleotide can be modified: phosphorothioate, instead of a regular phosphate group, can have a 2′ hydroxyl group (ribose usage), which will be methylated or have a 2′-4′ bond. ASOs function through several mechanisms, including triggering RNase H to cleave DNA/RNA hybrids.157

The first approved ASO drug, fomivirsen (brand name: Vitravene) in 1998, was used against human cytomegalovirus.158

It has been demonstrated that suppressing miR-33 by miR-33 ASOs, which are delivered to macrophages by pH low-insertion peptides, decreases lipid accumulation in vascular lesions in mice.159

Vupanorsen, also known as AKCEA-ANGPTL3-LRx, is an ASO that targets and inhibits the production of angiopoietin-like 3 (ANGPTL3) in the liver by binding to ANGPTL3 mRNA. The ANGPTL3 protein inhibits lipoprotein lipase and endothelial lipase, and inhibition of this protein has been shown to reduce triglyceride and non-high-density lipoprotein cholesterol levels.160 However, these reductions were not sufficient. Additionally, vupanorsen was associated with elevated liver fat, aminotransferase and aspartate aminotransferase levels. Due to these discouraging outcomes, it was announced on January 31, 2022, that the development of vupanorsen was discontinued.161

miRNA sponges contain complementary sites to specific miRNAs. Moreover, they suppress the levels of target miRNAs that are complementary to them. It has been shown that lncRNAs and circRNAs can act as miRNA sponges.162,163

Different delivery systems, including dendrimers, exosomes, polymeric nanoparticles, PEG/PEI nanoparticles, and rod nanocrystals, have been utilized for delivering ncRNAs to corresponding targets.164 Despite the potential of ncRNAs as therapeutic agents against atherosclerosis, challenges persist in their application. These challenges encompass the chemical instability of a particular ncRNA, extracellular and intracellular barriers for the delivery of ncRNAs, immunogenicity problems (pro-inflammatory cytokine production, NF-kB activation, RNA interference), and off-target effects.164

Conclusions

The study of ncRNAs has gained significant attention in the last decade due to their involvement in different processes, including the progression of various diseases. ncRNAs hold great promise as therapeutic targets for a wide range of diseases. Various ncRNAs crucial in regulating different cellular processes have been identified, and mutations or abnormal expression of ncRNAs can result in the development of diseases, including atherosclerosis. ncRNAs regulate different aspects of atherosclerosis, such as lipid metabolism, inflammation, and SMC proliferation. Numerous studies have demonstrated the therapeutic potential of targeting ncRNAs through various approaches. However, despite the promise, there are currently limited approved drugs against atherosclerosis based on ncRNAs. Many RNA therapeutics are either under development or have been discontinued. Drugs based on siRNAs and ASOs have been successfully used because they can target specific genes effectively. LncRNAs and circRNAs also play important roles in atherosclerosis development and present potential as treatment targets.

Abbreviations

ABC: 

ATP-binding cassette

ABCA1: 

ABC subfamily A member 1

ABCG1: 

ABC subfamily G member 1

ACC: 

acetyl-CoA carboxylase

ANGPTL3: 

angiopoietin-like 3

ApoE: 

apolipoprotein E

ASO: 

antisense oligonucleotide

CCND1: 

cyclin D1

CDC42: 

cell division cycle 42

circRNA: 

circular RNA

CVD: 

cardiovascular disease

CXCL10: 

C-X-C motif chemokine ligand 10

CXCR4: 

C-X-C motif chemokine receptor 4

DDX17: 

DEAD-box helicase 17

dsRNA: 

double-stranded RNA

EMT: 

epithelial-mesenchymal transition

EndMT: 

endothelial-mesenchymal transition

EPLIN: 

epithelial protein lost in neoplasm beta

FGF1: 

fibroblast growth factor 1

HDAC: 

histone deacetylase

HIF-1: 

hypoxia inducible factor-1

IL: 

interleukin

IRAK1: 

interleukin 1 receptor associated kinase 1

KLF: 

Kruppel-like factor

LDL: 

low-density lipoprotein

lncRNA: 

long non-coding RNA

MEOX2: 

mesenchyme homeobox 2

MeXis: 

macrophage-expressed LXR-induced sequence

miRNA: 

microRNA

MMP2: 

matrix metallopeptidase 2

mRNA: 

messenger RNA

mtDNA: 

mitochondrial DNA

MV: 

microvesicle

MVB: 

multivesicular body

ncRNA: 

non-coding RNA

NF-kB: 

nuclear factor kappa B

NOS3: 

nitric oxide synthase 3

NPC1: 

Niemann-Pick type C1

oxLDL: 

oxidized LDL

PKD1: 

polycystic kidney disease 1

pre-miRNA: 

precursor miRNA

pri-miRNA: 

primary miRNA

PTEN: 

phosphatase and tensin homolog

RISC: 

RNA-induced silencing complex

RNCR3: 

retinal non-coding RNA3

ROS: 

reactive oxygen species

SCD: 

stearoyl-CoA desaturase

siRNA: 

small interfering RNA

SMC: 

smooth muscle cell

sncRNA: 

small non-coding RNA

SOCS1: 

suppressor of cytokine signaling 1

SREBP: 

sterol regulatory element-binding protein

STAT3: 

signal transducer and activator of transcription 3

THBS1: 

thrombospondin 1

TNFα: 

tumor necrosis factor

TRAF6: 

TNF receptor associated factor 6

VEGF: 

vascular endothelial growth factor

Declarations

Acknowledgement

None.

Funding

This research was funded by the Russian Science Foundation, grant number 22-25-00457.

Conflict of interest

The authors declare no conflict of interests.

Authors’ contributions

Searched the literature and prepared draft (AA), figures preparation (AA, EG), reviewed the literature and improved the manuscript (AA, EB, EG, AG, DB), conceived, designed, and edited the manuscript and supervised the study (EB). All authors have read and approved the manuscript.

References

  1. Zhang P, Wu W, Chen Q, Chen M. Non-Coding RNAs and their Integrated Networks. J Integr Bioinform 2019;16(3):2019-0027 View Article PubMed/NCBI
  2. Wang M, Yu F, Wu W, Zhang Y, Chang W, Ponnusamy M, et al. Circular RNAs: A novel type of non-coding RNA and their potential implications in antiviral immunity. Int J Biol Sci 2017;13(12):1497-1506 View Article PubMed/NCBI
  3. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004;116(2):281-297 View Article PubMed/NCBI
  4. Eulalio A, Huntzinger E, Nishihara T, Rehwinkel J, Fauser M, Izaurralde E. Deadenylation is a widespread effect of miRNA regulation. RNA 2009;15(1):21-32 View Article PubMed/NCBI
  5. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993;75(5):843-854 View Article PubMed/NCBI
  6. Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 1993;75(5):855-862 View Article PubMed/NCBI
  7. Mack GS. MicroRNA gets down to business. Nat Biotechnol 2007;25(6):631-638 View Article PubMed/NCBI
  8. Bhat SA, Ahmad SM, Mumtaz PT, Malik AA, Dar MA, Urwat U, et al. Long non-coding RNAs: Mechanism of action and functional utility. Noncoding RNA Res 2016;1(1):43-50 View Article PubMed/NCBI
  9. Guo CJ, Ma XK, Xing YH, Zheng CC, Xu YF, Shan L, et al. Distinct Processing of lncRNAs Contributes to Non-conserved Functions in Stem Cells. Cell 2020;181(3):621-636.e22 View Article PubMed/NCBI
  10. Khyzha N, Alizada A, Wilson MD, Fish JE. Epigenetics of Atherosclerosis: Emerging Mechanisms and Methods. Trends Mol Med 2017;23(4):332-347 View Article PubMed/NCBI
  11. Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol 2021;22(2):96-118 View Article PubMed/NCBI
  12. Guil S, Esteller M. Cis-acting noncoding RNAs: Friends and foes. Nat Struct Mol Biol 2012;19(11):1068-1075 View Article PubMed/NCBI
  13. Portoso M, Ragazzini R, Brenčič Ž, Moiani A, Michaud A, Vassilev I, et al. PRC2 is dispensable for HOTAIR-mediated transcriptional repression. EMBO J 2017;36(8):981-994 View Article PubMed/NCBI
  14. Rayner KJ, Suárez Y, Dávalos A, Parathath S, Fitzgerald ML, Tamehiro N, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 2010;328(5985):1570-1573 View Article PubMed/NCBI
  15. Madison BB. Srebp2: A master regulator of sterol and fatty acid synthesis. J Lipid Res 2016;57(3):333-335 View Article PubMed/NCBI
  16. Rader DJ, Hovingh GK. HDL and cardiovascular disease. Lancet 2014;384(9943):618-625 View Article PubMed/NCBI
  17. Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszten RE, et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 2010;328(5985):1566-1569 View Article PubMed/NCBI
  18. Fernández-Hernando C, Suárez Y, Rayner KJ, Moore KJ. MicroRNAs in lipid metabolism. Curr Opin Lipidol 2011;22(2):86-92 View Article PubMed/NCBI
  19. Goedeke L, Rotllan N, Canfrán-Duque A, Aranda JF, Ramírez CM, Araldi E, et al. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med 2015;21(11):1280-1289 View Article PubMed/NCBI
  20. Sun D, Zhang J, Xie J, Wei W, Chen M, Zhao X. MiR-26 controls LXR-dependent cholesterol efflux by targeting ABCA1 and ARL7. FEBS Lett 2012;586(10):1472-1479 View Article PubMed/NCBI
  21. Ramirez CM, Dávalos A, Goedeke L, Salerno AG, Warrier N, Cirera-Salinas D, et al. MicroRNA-758 regulates cholesterol efflux through posttranscriptional repression of ATP-binding cassette transporter A1. Arterioscler Thromb Vasc Biol 2011;31(11):2707-2714 View Article PubMed/NCBI
  22. Sallam T, Jones M, Thomas BJ, Wu X, Gilliland T, Qian K, et al. Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA. Nat Med 2018;24(3):304-312 View Article PubMed/NCBI
  23. Guo J, Fang W, Sun L, Lu Y, Dou L, Huang X, et al. Ultraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation. Nat Commun 2018;9(1):612 View Article PubMed/NCBI
  24. Wang W, Yang N, Yang YH, Wen R, Liu CF, Zhang TN. Non-Coding RNAs: Master Regulators of Inflammasomes in Inflammatory Diseases. J Inflamm Res 2021;14:5023-5050 View Article PubMed/NCBI
  25. Marques-Rocha JL, Samblas M, Milagro FI, Bressan J, Martínez JA, Marti A. Noncoding RNAs, cytokines, and inflammation-related diseases. FASEB J 2015;29(9):3595-3611 View Article PubMed/NCBI
  26. Chini A, Guha P, Malladi VS, Guo Z, Mandal SS. Novel long non-coding RNAs associated with inflammation and macrophage activation in human. Sci Rep 2023;13(1):4036 View Article PubMed/NCBI
  27. Wu WH, Hu CP, Chen XP, Zhang WF, Li XW, Xiong XM, et al. MicroRNA-130a mediates proliferation of vascular smooth muscle cells in hypertension. Am J Hypertens 2011;24(10):1087-1093 View Article PubMed/NCBI
  28. Sun SG, Zheng B, Han M, Fang XM, Li HX, Miao SB, et al. miR-146a and Krüppel-like factor 4 form a feedback loop to participate in vascular smooth muscle cell proliferation. EMBO Rep 2011;12(1):56-62 View Article PubMed/NCBI
  29. Shan K, Jiang Q, Wang XQ, Wang YN, Yang H, Yao MD, et al. Role of long non-coding RNA-RNCR3 in atherosclerosis-related vascular dysfunction. Cell Death Dis 2016;7(6):e2248 View Article PubMed/NCBI
  30. Yu X, Zhang L, Wen G, Zhao H, Luong LA, Chen Q, et al. Upregulated sirtuin 1 by miRNA-34a is required for smooth muscle cell differentiation from pluripotent stem cells. Cell Death Differ 2015;22(7):1170-1180 View Article PubMed/NCBI
  31. Ballantyne MD, Pinel K, Dakin R, Vesey AT, Diver L, Mackenzie R, et al. Smooth Muscle Enriched Long Noncoding RNA (SMILR) Regulates Cell Proliferation. Circulation 2016;133(21):2050-2065 View Article PubMed/NCBI
  32. Zhang M, He J, Jiang C, Zhang W, Yang Y, Wang Z, et al. Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy. Int J Nanomedicine 2017;12:533-558 View Article PubMed/NCBI
  33. Zhang H, Liu Y, Yan L, Wang S, Zhang M, Ma C, et al. Long noncoding RNA Hoxaas3 contributes to hypoxia-induced pulmonary artery smooth muscle cell proliferation. Cardiovasc Res 2019;115(3):647-657 View Article PubMed/NCBI
  34. Wu G, Cai J, Han Y, Chen J, Huang ZP, Chen C, et al. LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity. Circulation 2014;130(17):1452-1465 View Article PubMed/NCBI
  35. Zhang L, Huang D, Wang Q, Shen D, Wang Y, Chen B, et al. MiR-132 inhibits expression of SIRT1 and induces pro-inflammatory processes of vascular endothelial inflammation through blockade of the SREBP-1c metabolic pathway. Cardiovasc Drugs Ther 2014;28(4):303-311 View Article PubMed/NCBI
  36. Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci USA 2008;105(5):1516-1521 View Article PubMed/NCBI
  37. Cai Y, Zhang Y, Chen H, Sun XH, Zhang P, Zhang L, et al. MicroRNA-17-3p suppresses NF-κB-mediated endothelial inflammation by targeting NIK and IKKβ binding protein. Acta Pharmacol Sin 2021;42(12):2046-2057 View Article PubMed/NCBI
  38. Liu RR, Li J, Gong JY, Kuang F, Liu JY, Zhang YS, et al. MicroRNA-141 regulates the expression level of ICAM-1 on endothelium to decrease myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2015;309(8):H1303-H1313 View Article PubMed/NCBI
  39. Duan M, Yao H, Hu G, Chen X, Lund AK, Buch S. HIV Tat induces expression of ICAM-1 in HUVECs: implications for miR-221/-222 in HIV-associated cardiomyopathy. PLoS One 2013;8(3):e60170 View Article PubMed/NCBI
  40. Zhong L, Simoneau B, Huot J, Simard MJ. p38 and JNK pathways control E-selectin-dependent extravasation of colon cancer cells by modulating miR-31 transcription. Oncotarget 2017;8(1):1678-1687 View Article PubMed/NCBI
  41. Bhaumik D, Scott GK, Schokrpur S, Patil CK, Orjalo AV, Rodier F, et al. MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging (Albany NY) 2009;1(4):402-411 View Article PubMed/NCBI
  42. Pankratz F, Hohnloser C, Bemtgen X, Jaenich C, Kreuzaler S, Hoefer I, et al. MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy. Circ Res 2018;122(3):417-432 View Article PubMed/NCBI
  43. Liu LZ, Li C, Chen Q, Jing Y, Carpenter R, Jiang Y, et al. MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1α expression. PLoS One 2011;6(4):e19139 View Article PubMed/NCBI
  44. Liu Y, Luo F, Wang B, Li H, Xu Y, Liu X, et al. STAT3-regulated exosomal miR-21 promotes angiogenesis and is involved in neoplastic processes of transformed human bronchial epithelial cells. Cancer Lett 2016;370(1):125-135 View Article PubMed/NCBI
  45. Hu H, Wang B, Jiang C, Li R, Zhao J. Endothelial progenitor cell-derived exosomes facilitate vascular endothelial cell repair through shuttling miR-21-5p to modulate Thrombospondin-1 expression. Clin Sci (Lond) 2019;133(14):1629-1644 View Article PubMed/NCBI
  46. Jing BQ, Ou Y, Zhao L, Xie Q, Zhang YX. Experimental study on the prevention of liver cancer angiogenesis via miR-126. Eur Rev Med Pharmacol Sci 2017;21(22):5096-5100 View Article PubMed/NCBI
  47. Alhasan L. MiR-126 Modulates Angiogenesis in Breast Cancer by Targeting VEGF-A -mRNA. Asian Pac J Cancer Prev 2019;20(1):193-197 View Article PubMed/NCBI
  48. Huang TH, Chu TY. Repression of miR-126 and upregulation of adrenomedullin in the stromal endothelium by cancer-stromal cross talks confers angiogenesis of cervical cancer. Oncogene 2014;33(28):3636-3647 View Article PubMed/NCBI
  49. Du C, Lv Z, Cao L, Ding C, Gyabaah OA, Xie H, et al. MiR-126-3p suppresses tumor metastasis and angiogenesis of hepatocellular carcinoma by targeting LRP6 and PIK3R2. J Transl Med 2014;12:259 View Article PubMed/NCBI
  50. Ashrafizadeh M, Najafi M, Mohammadinejad R, Farkhondeh T, Samarghandian S. Flaming the fight against cancer cells: the role of microRNA-93. Cancer Cell Int 2020;20:277 View Article PubMed/NCBI
  51. Liang L, Zhao L, Zan Y, Zhu Q, Ren J, Zhao X. MiR-93-5p enhances growth and angiogenesis capacity of HUVECs by down-regulating EPLIN. Oncotarget 2017;8(63):107033-107043 View Article PubMed/NCBI
  52. Fang L, Du WW, Yang W, Rutnam ZJ, Peng C, Li H, et al. MiR-93 enhances angiogenesis and metastasis by targeting LATS2. Cell Cycle 2012;11(23):4352-4365 View Article PubMed/NCBI
  53. Fabbri E, Brognara E, Montagner G, Ghimenton C, Eccher A, Cantù C, et al. Regulation of IL-8 gene expression in gliomas by microRNA miR-93. BMC Cancer 2015;15:661 View Article PubMed/NCBI
  54. Conigliaro A, Costa V, Lo Dico A, Saieva L, Buccheri S, Dieli F, et al. CD90+ liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA. Mol Cancer 2015;14:155 View Article PubMed/NCBI
  55. Zhou YH, Cui YH, Wang T, Luo Y. Long non-coding RNA HOTAIR in cervical cancer: Molecular marker, mechanistic insight, and therapeutic target. Adv Clin Chem 2020;97:117-140 View Article PubMed/NCBI
  56. Yuan SX, Yang F, Yang Y, Tao QF, Zhang J, Huang G, et al. Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients’ poor recurrence-free survival after hepatectomy. Hepatology 2012;56(6):2231-2241 View Article PubMed/NCBI
  57. Liu ZZ, Tian YF, Wu H, Ouyang SY, Kuang WL. LncRNA H19 promotes glioma angiogenesis through miR-138/HIF-1α/VEGF axis. Neoplasma 2020;67(1):111-118 View Article PubMed/NCBI
  58. Fu WM, Lu YF, Hu BG, Liang WC, Zhu X, Yang HD, et al. Long noncoding RNA Hotair mediated angiogenesis in nasopharyngeal carcinoma by direct and indirect signaling pathways. Oncotarget 2016;7(4):4712-4723 View Article PubMed/NCBI
  59. Wang Y, Wu Y, Xiao K, Zhao Y, Lv G, Xu S, et al. RPS24c Isoform Facilitates Tumor Angiogenesis Via Promoting the Stability of MVIH in Colorectal Cancer. Curr Mol Med 2020;20(5):388-395 View Article PubMed/NCBI
  60. Leisegang MS, Fork C, Josipovic I, Richter FM, Preussner J, Hu J, et al. Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function. Circulation 2017;136(1):65-79 View Article PubMed/NCBI
  61. Liu X, Shen S, Zhu L, Su R, Zheng J, Ruan X, et al. SRSF10 inhibits biogenesis of circ-ATXN1 to regulate glioma angiogenesis via miR-526b-3p/MMP2 pathway. J Exp Clin Cancer Res 2020;39(1):121 View Article PubMed/NCBI
  62. Xie M, Yu T, Jing X, Ma L, Fan Y, Yang F, et al. Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation. Mol Cancer 2020;19(1):112 View Article PubMed/NCBI
  63. Cai F, Fu W, Tang L, Tang J, Sun J, Fu G, et al. Hsa_circ_0000515 is a novel circular RNA implicated in the development of breast cancer through its regulation of the microRNA-296-5p/CXCL10 axis. FEBS J 2021;288(3):861-883 View Article PubMed/NCBI
  64. Zheng X, Ma YF, Zhang XR, Li Y, Zhao HH, Han SG. Circ_0056618 promoted cell proliferation, migration and angiogenesis through sponging with miR-206 and upregulating CXCR4 and VEGF-A in colorectal cancer. Eur Rev Med Pharmacol Sci 2020;24(8):4190-4202 View Article PubMed/NCBI
  65. Li W, Yang FQ, Sun CM, Huang JH, Zhang HM, Li X, et al. circPRRC2A promotes angiogenesis and metastasis through epithelial-mesenchymal transition and upregulates TRPM3 in renal cell carcinoma. Theranostics 2020;10(10):4395-4409 View Article PubMed/NCBI
  66. Zhong Z, Huang M, Lv M, He Y, Duan C, Zhang L, et al. Circular RNA MYLK as a competing endogenous RNA promotes bladder cancer progression through modulating VEGFA/VEGFR2 signaling pathway. Cancer Lett 2017;403:305-317 View Article PubMed/NCBI
  67. He Q, Zhao L, Liu X, Zheng J, Liu Y, Liu L, et al. MOV10 binding circ-DICER1 regulates the angiogenesis of glioma via miR-103a-3p/miR-382-5p mediated ZIC4 expression change. J Exp Clin Cancer Res 2019;38(1):9 View Article PubMed/NCBI
  68. Malekmohammad K, Bezsonov EE, Rafieian-Kopaei M. Role of Lipid Accumulation and Inflammation in Atherosclerosis: Focus on Molecular and Cellular Mechanisms. Front Cardiovasc Med 2021;8:707529 View Article PubMed/NCBI
  69. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012;32(9):2045-2051 View Article PubMed/NCBI
  70. Getz GS, Reardon CA. Animal models of atherosclerosis. Arterioscler Thromb Vasc Biol 2012;32(5):1104-1115 View Article PubMed/NCBI
  71. Vergeer M, Holleboom AG, Kastelein JJ, Kuivenhoven JA. The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?. J Lipid Res 2010;51(8):2058-2073 View Article PubMed/NCBI
  72. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb 1994;14(1):133-140 View Article PubMed/NCBI
  73. Ishibashi S, Goldstein JL, Brown MS, Herz J, Burns DK. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest 1994;93(5):1885-1893 View Article PubMed/NCBI
  74. Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W, Rosenfeld ME, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1994;89(5):2462-2478 View Article PubMed/NCBI
  75. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995;92(5):1355-1374 View Article PubMed/NCBI
  76. Mezentsev A, Bezsonov E, Kashirskikh D, Baig MS, Eid AH, Orekhov A. Proatherogenic Sialidases and Desialylated Lipoproteins: 35 Years of Research and Current State from Bench to Bedside. Biomedicines 2021;9(6):600 View Article PubMed/NCBI
  77. Mushenkova NV, Bezsonov EE, Orekhova VA, Popkova TV, Starodubova AV, Orekhov AN. Recognition of Oxidized Lipids by Macrophages and Its Role in Atherosclerosis Development. Biomedicines 2021;9(8):915 View Article PubMed/NCBI
  78. Leitinger N. Oxidized phospholipids as modulators of inflammation in atherosclerosis. Curr Opin Lipidol 2003;14(5):421-430 View Article PubMed/NCBI
  79. Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol 1998;18(5):842-851 View Article PubMed/NCBI
  80. Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L, Beaudet AL. P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J Exp Med 2000;191(1):189-194 View Article PubMed/NCBI
  81. Cybulsky MI, Gimbrone MA. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 1991;251(4995):788-791 View Article PubMed/NCBI
  82. Ivanova EA, Myasoedova VA, Melnichenko AA, Grechko AV, Orekhov AN. Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases. Oxid Med Cell Longev 2017;2017:1273042 View Article PubMed/NCBI
  83. Lao KH, Zeng L, Xu Q. Endothelial and smooth muscle cell transformation in atherosclerosis. Curr Opin Lipidol 2015;26(5):449-456 View Article PubMed/NCBI
  84. Ohta S, Suzuki K, Tachibana K, Tanaka H, Yamada G. Cessation of gastrulation is mediated by suppression of epithelial-mesenchymal transition at the ventral ectodermal ridge. Development 2007;134(24):4315-4324 View Article PubMed/NCBI
  85. Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Müller GA, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int 2002;61(5):1714-1728 View Article PubMed/NCBI
  86. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009;119(6):1420-1428 View Article PubMed/NCBI
  87. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 2007;13(8):952-961 View Article PubMed/NCBI
  88. Chen PY, Qin L, Baeyens N, Li G, Afolabi T, Budatha M, et al. Endothelial-to-mesenchymal transition drives atherosclerosis progression. J Clin Invest 2015;125(12):4514-4528 View Article PubMed/NCBI
  89. Lecce L, Xu Y, V’Gangula B, Chandel N, Pothula V, Caudrillier A, et al. Histone deacetylase 9 promotes endothelial-mesenchymal transition and an unfavorable atherosclerotic plaque phenotype. J Clin Invest 2021;131(15):e131178 View Article PubMed/NCBI
  90. Poznyak AV, Bezsonov EE, Popkova TV, Starodubova AV, Orekhov AN. Immunity in Atherosclerosis: Focusing on T and B Cells. Int J Mol Sci 2021;22(16):8379 View Article PubMed/NCBI
  91. Fernandez DM, Rahman AH, Fernandez NF, Chudnovskiy A, Amir ED, Amadori L, et al. Single-cell immune landscape of human atherosclerotic plaques. Nat Med 2019;25(10):1576-1588 View Article PubMed/NCBI
  92. Pattarabanjird T, Li C, McNamara C. B Cells in Atherosclerosis: Mechanisms and Potential Clinical Applications. JACC Basic Transl Sci 2021;6(6):546-563 View Article PubMed/NCBI
  93. Upadhye A, Srikakulapu P, Gonen A, Hendrikx S, Perry HM, Nguyen A, et al. Diversification and CXCR4-Dependent Establishment of the Bone Marrow B-1a Cell Pool Governs Atheroprotective IgM Production Linked to Human Coronary Atherosclerosis. Circ Res 2019;125(10):e55-e70 View Article PubMed/NCBI
  94. Bezsonov EE, Sobenin IA, Orekhov AN. Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology. Int J Mol Sci 2021;22(8):4080 View Article PubMed/NCBI
  95. Salnikova D, Orekhova V, Grechko A, Starodubova A, Bezsonov E, Popkova T, et al. Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis. Int J Mol Sci 2021;22(16):8990 View Article PubMed/NCBI
  96. Sazonova MA, Ryzhkova AI, Sinyov VV, Sazonova MD, Nikitina NN, Shkurat TP, et al. Mitochondrial mutations associated with cardiac angina. Vessel Plus 2019;3:8 View Article
  97. Sobenin IA, Sazonova MA, Postnov AY, Salonen JT, Bobryshev YV, Orekhov AN. Association of mitochondrial genetic variation with carotid atherosclerosis. PLoS One 2013;8(7):e68070 View Article PubMed/NCBI
  98. Sobenin IA, Sazonova MA, Postnov AY, Bobryshev YV, Orekhov AN. Mitochondrial mutations are associated with atherosclerotic lesions in the human aorta. Clin Dev Immunol 2012;2012:832464 View Article PubMed/NCBI
  99. Naik E, Dixit VM. Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J Exp Med 2011;208(3):417-420 View Article PubMed/NCBI
  100. Nakahira K, Hisata S, Choi AM. The Roles of Mitochondrial Damage-Associated Molecular Patterns in Diseases. Antioxid Redox Signal 2015;23(17):1329-1350 View Article PubMed/NCBI
  101. Mathew A, Lindsley TA, Sheridan A, Bhoiwala DL, Hushmendy SF, Yager EJ, et al. Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern (DAMP) family and possible trigger of neurodegeneration. J Alzheimers Dis 2012;30(3):617-627 View Article PubMed/NCBI
  102. Alqahtani T, Deore SL, Kide AA, Shende BA, Sharma R, Dadarao Chakole R, et al. Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease, and Parkinson’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis -An updated review. Mitochondrion 2023;71:83-92 View Article PubMed/NCBI
  103. Dabravolski SA, Orekhova VA, Baig MS, Bezsonov EE, Starodubova AV, Popkova TV, et al. The Role of Mitochondrial Mutations and Chronic Inflammation in Diabetes. Int J Mol Sci 2021;22(13):6733 View Article PubMed/NCBI
  104. Chen X, Ji Y, Liu R, Zhu X, Wang K, Yang X, et al. Mitochondrial dysfunction: roles in skeletal muscle atrophy. J Transl Med 2023;21(1):503 View Article PubMed/NCBI
  105. Dabravolski SA, Bezsonov EE, Orekhov AN. The role of mitochondria dysfunction and hepatic senescence in NAFLD development and progression. Biomed Pharmacother 2021;142:112041 View Article PubMed/NCBI
  106. Dabravolski SA, Bezsonov EE, Baig MS, Popkova TV, Nedosugova LV, Starodubova AV, et al. Mitochondrial Mutations and Genetic Factors Determining NAFLD Risk. Int J Mol Sci 2021;22(9):4459 View Article PubMed/NCBI
  107. Beheshti SA, Shamsasenjan K, Ahmadi M, Abbasi B. CAR Treg: A new approach in the treatment of autoimmune diseases. Int Immunopharmacol 2022;102:108409 View Article PubMed/NCBI
  108. Koushki K, Keshavarz Shahbaz S, Keshavarz M, Bezsonov EE, Sathyapalan T, Sahebkar A. Gold Nanoparticles: Multifaceted Roles in the Management of Autoimmune Disorders. Biomolecules 2021;11(9):1289 View Article PubMed/NCBI
  109. Cinoku II, Mavragani CP, Moutsopoulos HM. Atherosclerosis: Beyond the lipid storage hypothesis. The role of autoimmunity. Eur J Clin Invest 2020;50(2):e13195 View Article PubMed/NCBI
  110. Matsuura E, Kobayashi K, Tabuchi M, Lopez LR. Oxidative modification of low-density lipoprotein and immune regulation of atherosclerosis. Prog Lipid Res 2006;45(6):466-486 View Article PubMed/NCBI
  111. van Tits L, de Graaf J, Toenhake H, van Heerde W, Stalenhoef A. C-reactive protein and annexin A5 bind to distinct sites of negatively charged phospholipids present in oxidized low-density lipoprotein. Arterioscler Thromb Vasc Biol 2005;25(4):717-722 View Article PubMed/NCBI
  112. Wang Y, Feng X, Shen B, Ma J, Zhao W. Is Vascular Amyloidosis Intertwined with Arterial Aging, Hypertension and Atherosclerosis?. Front Genet 2017;8:126 View Article PubMed/NCBI
  113. Röcken C, Tautenhahn J, Bühling F, Sachwitz D, Vöckler S, Goette A, et al. Prevalence and pathology of amyloid in atherosclerotic arteries. Arterioscler Thromb Vasc Biol 2006;26(3):676-677 View Article PubMed/NCBI
  114. Kalback W, Esh C, Castaño EM, Rahman A, Kokjohn T, Luehrs DC, et al. Atherosclerosis, vascular amyloidosis and brain hypoperfusion in the pathogenesis of sporadic Alzheimer’s disease. Neurol Res 2004;26(5):525-539 View Article PubMed/NCBI
  115. Simons JP, Al-Shawi R, Ellmerich S, Speck I, Aslam S, Hutchinson WL, et al. Pathogenetic mechanisms of amyloid A amyloidosis. Proc Natl Acad Sci U S A 2013;110(40):16115-16120 View Article PubMed/NCBI
  116. Falk RH, Alexander KM, Liao R, Dorbala S. AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy. J Am Coll Cardiol 2016;68(12):1323-1341 View Article PubMed/NCBI
  117. Wickner RB, Bezsonov EE, Son M, Ducatez M, DeWilde M, Edskes HK. Anti-Prion Systems in Yeast and Inositol Polyphosphates. Biochemistry 2018;57(8):1285-1292 View Article PubMed/NCBI
  118. Bezsonov EE, Groenning M, Galzitskaya OV, Gorkovskii AA, Semisotnov GV, Selyakh IO, et al. Amyloidogenic peptides of yeast cell wall glucantransferase Bgl2p as a model for the investigation of its pH-dependent fibril formation. Prion 2013;7(2):175-184 View Article PubMed/NCBI
  119. Tang Y, Li H, Chen C. Non-coding RNA-Associated Therapeutic Strategies in Atherosclerosis. Front Cardiovasc Med 2022;9:889743 View Article PubMed/NCBI
  120. Nakashima Y, Chen YX, Kinukawa N, Sueishi K. Distributions of diffuse intimal thickening in human arteries: preferential expression in atherosclerosis-prone arteries from an early age. Virchows Arch 2002;441(3):279-288 View Article PubMed/NCBI
  121. Nakashima Y, Wight TN, Sueishi K. Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans. Cardiovasc Res 2008;79(1):14-23 View Article PubMed/NCBI
  122. Gimbrone MA, García-Cardeña G. Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circ Res 2016;118(4):620-636 View Article PubMed/NCBI
  123. Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, et al. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res 2011;108(2):235-248 View Article PubMed/NCBI
  124. Bäck M, Yurdagul A, Tabas I, Öörni K, Kovanen PT. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol 2019;16(7):389-406 View Article PubMed/NCBI
  125. Soehnlein O, Libby P. Targeting inflammation in atherosclerosis - from experimental insights to the clinic. Nat Rev Drug Discov 2021;20(8):589-610 View Article PubMed/NCBI
  126. Wei Y, Zhu M, Corbalán-Campos J, Heyll K, Weber C, Schober A. Regulation of Csf1r and Bcl6 in macrophages mediates the stage-specific effects of microRNA-155 on atherosclerosis. Arterioscler Thromb Vasc Biol 2015;35(4):796-803 View Article PubMed/NCBI
  127. Doyle LM, Wang MZ. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells 2019;8(7):727 View Article PubMed/NCBI
  128. Hanson PI, Cashikar A. Multivesicular body morphogenesis. Annu Rev Cell Dev Biol 2012;28:337-362 View Article PubMed/NCBI
  129. Zhang Y, Bi J, Huang J, Tang Y, Du S, Li P. Exosome: A Review of Its Classification, Isolation Techniques, Storage, Diagnostic and Targeted Therapy Applications. Int J Nanomedicine 2020;15:6917-6934 View Article PubMed/NCBI
  130. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013;200(4):373-383 View Article PubMed/NCBI
  131. Jiapaer Z, Li C, Yang X, Sun L, Chatterjee E, Zhang L, et al. Extracellular Non-Coding RNAs in Cardiovascular Diseases. Pharmaceutics 2023;15(1):155 View Article PubMed/NCBI
  132. Chen JF, Murchison EP, Tang R, Callis TE, Tatsuguchi M, Deng Z, et al. Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. Proc Natl Acad Sci USA 2008;105(6):2111-2116 View Article PubMed/NCBI
  133. Wang X, Lian Y, Wen X, Guo J, Wang Z, Jiang S, et al. Expression of miR-126 and its potential function in coronary artery disease. Afr Health Sci 2017;17(2):474-480 View Article PubMed/NCBI
  134. Gao W, He HW, Wang ZM, Zhao H, Lian XQ, Wang YS, et al. Plasma levels of lipometabolism-related miR-122 and miR-370 are increased in patients with hyperlipidemia and associated with coronary artery disease. Lipids Health Dis 2012;11:55 View Article PubMed/NCBI
  135. van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J, Gerard RD, et al. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA 2006;103(48):18255-18260 View Article PubMed/NCBI
  136. Poller W, Dimmeler S, Heymans S, Zeller T, Haas J, Karakas M, et al. Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives. Eur Heart J 2018;39(29):2704-2716 View Article PubMed/NCBI
  137. Kumar S, Kim CW, Simmons RD, Jo H. Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis: mechanosensitive athero-miRs. Arterioscler Thromb Vasc Biol 2014;34(10):2206-2216 View Article PubMed/NCBI
  138. Fang Y, Davies PF. Site-specific microRNA-92a regulation of Kruppel-like factors 4 and 2 in atherosusceptible endothelium. Arterioscler Thromb Vasc Biol 2012;32(4):979-987 View Article PubMed/NCBI
  139. Loyer X, Potteaux S, Vion AC, Guérin CL, Boulkroun S, Rautou PE, et al. Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice. Circ Res 2014;114(3):434-443 View Article PubMed/NCBI
  140. Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CD, et al. MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells. Immunity 2011;35(2):169-181 View Article PubMed/NCBI
  141. Chong MM, Rasmussen JP, Rudensky AY, Littman DR. The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J Exp Med 2008;205(9):2005-2017 View Article PubMed/NCBI
  142. Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, Rajewsky K. Aberrant T cell differentiation in the absence of Dicer. J Exp Med 2005;202(2):261-269 View Article PubMed/NCBI
  143. Tian L, De Hertogh G, Fedeli M, Staats KA, Schonefeldt S, Humblet-Baron S, et al. Loss of T cell microRNA provides systemic protection against autoimmune pathology in mice. J Autoimmun 2012;38(1):39-48 View Article PubMed/NCBI
  144. Collier SP, Collins PL, Williams CL, Boothby MR, Aune TM. Cutting edge: influence of Tmevpg1, a long intergenic noncoding RNA, on the expression of Ifng by Th1 cells. J Immunol 2012;189(5):2084-2088 View Article PubMed/NCBI
  145. Du F, Yu F, Wang Y, Hui Y, Carnevale K, Fu M, et al. MicroRNA-155 deficiency results in decreased macrophage inflammation and attenuated atherogenesis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2014;34(4):759-767 View Article PubMed/NCBI
  146. Wang YS, Wang HY, Liao YC, Tsai PC, Chen KC, Cheng HY, et al. MicroRNA-195 regulates vascular smooth muscle cell phenotype and prevents neointimal formation. Cardiovasc Res 2012;95(4):517-526 View Article PubMed/NCBI
  147. Joris V, Gomez EL, Menchi L, Lobysheva I, Di Mauro V, Esfahani H, et al. MicroRNA-199a-3p and MicroRNA-199a-5p Take Part to a Redundant Network of Regulation of the NOS (NO Synthase)/NO Pathway in the Endothelium. Arterioscler Thromb Vasc Biol 2018;38(10):2345-2357 View Article PubMed/NCBI
  148. Yang Y, Tang F, Wei F, Yang L, Kuang C, Zhang H, et al. Silencing of long non-coding RNA H19 downregulates CTCF to protect against atherosclerosis by upregulating PKD1 expression in ApoE knockout mice. Aging (Albany NY) 2019;11(22):10016-10030 View Article PubMed/NCBI
  149. Lam JK, Chow MY, Zhang Y, Leung SW. siRNA Versus miRNA as Therapeutics for Gene Silencing. Mol Ther Nucleic Acids 2015;4(9):e252 View Article PubMed/NCBI
  150. Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med 2018;379(1):11-21 View Article PubMed/NCBI
  151. O’Donoghue ML, Rosenson RS, Gencer B, López JAG, Lepor NE, Baum SJ, et al. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N Engl J Med 2022;387(20):1855-1864 View Article PubMed/NCBI
  152. Merćep I, Friščić N, Strikić D, Reiner Ž. Advantages and Disadvantages of Inclisiran: A Small Interfering Ribonucleic Acid Molecule Targeting PCSK9-A Narrative Review. Cardiovasc Ther 2022;2022:8129513 View Article PubMed/NCBI
  153. Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. N Engl J Med 2017;376(1):41-51 View Article PubMed/NCBI
  154. Leiter LA, Teoh H, Kallend D, Wright RS, Landmesser U, Wijngaard PLJ, et al. Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial. Diabetes Care 2019;42(1):173-176 View Article PubMed/NCBI
  155. Bijsterbosch MK, Manoharan M, Rump ET, De Vrueh RL, van Veghel R, Tivel KL, et al. In vivo fate of phosphorothioate antisense oligodeoxynucleotides: predominant uptake by scavenger receptors on endothelial liver cells. Nucleic Acids Res 1997;25(16):3290-3296 View Article PubMed/NCBI
  156. Brown DA, Kang SH, Gryaznov SM, DeDionisio L, Heidenreich O, Sullivan S, et al. Effect of phosphorothioate modification of oligodeoxynucleotides on specific protein binding. J Biol Chem 1994;269(43):26801-26805 PubMed/NCBI
  157. Dhuri K, Bechtold C, Quijano E, Pham H, Gupta A, Vikram A, et al. Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development. J Clin Med 2020;9(6):4 View Article PubMed/NCBI
  158. Perry CM, Balfour JA. Fomivirsen. Drugs 1999;57(3):375-380 View Article PubMed/NCBI
  159. Zhang X, Rotllan N, Canfrán-Duque A, Sun J, Toczek J, Moshnikova A, et al. Targeted Suppression of miRNA-33 Using pHLIP Improves Atherosclerosis Regression. Circ Res 2022;131(1):77-90 View Article PubMed/NCBI
  160. Gaudet D, Karwatowska-Prokopczuk E, Baum SJ, Hurh E, Kingsbury J, Bartlett VJ, Vupanorsen Study Investigators, et al. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur Heart J 2020;41(40):3936-3945 View Article PubMed/NCBI
  161. Gouni-Berthold I, Schwarz J, Berthold HK. Updates in Drug Treatment of Severe Hypertriglyceridemia. Curr Atheroscler Rep 2023;25(10):701-709 View Article PubMed/NCBI
  162. Calin GA, Liu CG, Ferracin M, Hyslop T, Spizzo R, Sevignani C, et al. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell 2007;12(3):215-229 View Article PubMed/NCBI
  163. Panda AC. Circular RNAs Act as miRNA Sponges. Adv Exp Med Biol 2018;1087:67-79 View Article PubMed/NCBI
  164. Li X, Qi H, Cui W, Wang Z, Fu X, Li T, et al. Recent advances in targeted delivery of non-coding RNA-based therapeutics for atherosclerosis. Mol Ther 2022;30(10):3118-3132 View Article PubMed/NCBI
Copyright © 2024 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Gene Expression
  • eISSN 1555-3884

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2639060
  • Visits today : 1066
Back to Top

Non-coding RNA and Atherosclerosis

Aram Adyan, Evgeny Bezsonov, Eugene Grebenshchikov, Alexandr Grinev, Denis Bogomolov
  • Reset Zoom
  • Download TIFF