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Table of Contents    
Year : 2017  |  Volume : 65  |  Issue : 4  |  Page : 718-728

Molecular mechanisms of the intracranial aneurysms and their association with the long noncoding ribonucleic acid ANRIL – A review of literature

Department of Neurosurgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong Province, China

Date of Web Publication5-Jul-2017

Correspondence Address:
Jiang Che
111 Liuhua Road, Guangzhou, Guangdong Province
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/neuroindia.NI_1074_15

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 » Abstract 

Long noncoding ribonucleic acids (RNAs) are important regulators of gene expression. Antisense noncoding RNA in the INK4 locus (ANRIL), which was coded on the Chr9p21.3 loci, participates in the pathogenesis of tumor, coronary artery disease, type 2 diabetes mellitus, and other diseases. A genome-wide association study indicated ANRIL to be a candidate gene that may lead to the development of an intracranial aneurysm (IA) formation. However, the detailed molecular mechanisms are unknown and have not been studied. Through reviewing the molecular mechanisms responsible for the development of IA and the regulation pathway of ANRIL, this paper presents four possible molecular mechanisms that may be responsible for the influence of ANRIL on the development of IAs, that is, cell cycling, Krüppel-like factor 2 (KLF2), caspase recruitment domain family member 8, and retinoid metabolism. ANRIL may become a molecular marker or therapeutic target of IA in the future. To the best of our knowledge, this is the first paper elucidating the molecular linkage between ANRIL and IAs.

Keywords: ANRIL, intracranial aneurysm, long noncoding RNA, ribonucleic acid

How to cite this article:
Che J. Molecular mechanisms of the intracranial aneurysms and their association with the long noncoding ribonucleic acid ANRIL – A review of literature. Neurol India 2017;65:718-28

How to cite this URL:
Che J. Molecular mechanisms of the intracranial aneurysms and their association with the long noncoding ribonucleic acid ANRIL – A review of literature. Neurol India [serial online] 2017 [cited 2022 May 25];65:718-28. Available from: https://www.neurologyindia.com/text.asp?2017/65/4/718/209469

Key Message:
Antisense noncoding RNA in the INK4 locus (ANRIL), which was coded on the Chr9p21.3 loci, has been found to be a candidate gene for the development of an intracranial aneurysm. The four possible molecular mechanisms of ANRIL on the development of intracranial aneurysms include its influence on cell cycling, Krόppel-like factor 2 (KLF2), caspase recruitment domain family member 8, and retinoid metabolism.

Intracranial aneurysms (IAs) are balloon or sac-like dilatations of cerebral arteries. These abnormalities, present in the cerebral vasculature, pose a potential risk of rupture leading to subarachnoid hemorrhage (SAH), which may have a >50% combined morbidity. It is estimated that the prevalence of IAs is seen in 5% of adults, and that the annual risk of rupture is approximately 0.7%.[1] Aneurysmal SAH has a mortality rate of up to 50%,[2] and the sudden death rate is estimated at 12.4%.[3]

The risk factors responsible for IA formation and rupture can be classified into two major groups, namely, the genetic factors and the environmental factors. Environmental factors primarily include smoking,[4] aging,[5] female gender,[6] hypertension,[7] and certain medicines.[8] The genetic basis of IA has been widely studied through twin studies, familial genetic analysis, and population-based genetic epidemiology. Researches implicated IA to be a multigenic disorder.[9] However, a lot of contradictory information exists in the literature and the exact genes as well as the underlying mechanisms that may enhance the risk of its development are poorly understood. Identifying the susceptible genetic variants and the molecular signaling pathways may facilitate an understanding of the mechanisms responsible for the development of IAs and help in the further development of medications that may be helpful in preventing its formation or in obliterating a formed aneurysm.

With the advent of genome-wide association study (GWAS), it is frequently reported that the long noncoding RNA, antisense noncoding RNA in the INK4 locus (ANRIL), has a significant association with an IA. However, the detailed mechanism has not been clarified. This paper reviewed the previous studies and proposed a potential molecular mechanism that defines the role of ANRIL in the development of IAs.

 » Molecular Mechanism of Intracranial Aneurysm Formation Top

Extracellular matrix and metalloproteinases

Due to the lack of the external elastic lamina and the presence of a thin adventitia, cerebral arteries are prone to injuries. Previous studies have shown that matrix metalloproteinases (MMPs), responsible for the breakdown of the extracellular matrix (ECM), were involved in the development and rupture of IAs. Expression in aneurysmal tissues of MMP-2 and MMP-9 are higher than those in normal cerebral arteries.[10] Furthermore, expression of MMP-9 is higher in ruptured IAs than in unruptured ones.[11] MMP-9 functions through the degradation of type IV collagen, proteoglycan core protein, and elastin. It is produced by inflammatory cells, especially macrophages, and is regulated by tumor necrosis factor (TNF)-α, platelet-derived growth factor, epidermal growth factor, and c-Jun N-terminal kinases (JNK).[11] In addition, MMP-9 plays a critical role in angiogenesis and tissue-remodeling [Table 1].
Table 1: Summary of molecules that participate in intracranial aneurysm formation/growth/rupture

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Growth factors

The decrease in transforming growth factor (TGF) α[12] and β expression in vessel walls might contribute to the IA formation via decreased matrix synthesis.[13] Vascular endothelial growth factor (VEGF) is excessively increased in patients harboring an IA and possibly plays a protective role by stimulating the proliferation of fibroblasts, endothelial cells (ECs), smooth muscle cells (SMCs), and endothelial progenitor cells (EPCs).[14] It is possibly associated with IA wall remodeling and cellular infiltration.[13] Basic fibroblast growth factors (bFGFs) may repair experimental IAs in rats through induction of the proliferative response of SMCs. A genome-wide linkage study suggested FGF1 to be a candidate gene of IA.[15] The upregulated expression of monocyte chemotactic protein 1 (MCP-1) may promote IA formation [16] and be a potential biomarkers for SAH [17] [Table 1].

Inflammation and tumor necrosis factor-α

In the process of IA formation, tumor necrosis factor-α (TNF-α) is expressed by endothelial cells (ECs) and leads to chronic inflammation, triggering EC dysfunction and apoptosis.[18] Its elevation also correlates with other risk factors for aneurysm formation, including hypertension,[19] hemodynamic stress,[19] smoking,[20] and aging.[19],[21] Furthermore, TNF-α elevates during aneurysmal growth and rupture, and the mechanism is supposed to be blood–brain barrier destruction, proinflammatory mediator influx, and vascular dilation.[18] TNF-α induces proinflammatory/matrix-remodeling phenotypic modulation of SMCs in cerebral vascular walls through myocardin and KLF4-regulated pathways.[19] TNF-α also regulates apoptosis of SMCs [22] [Table 1].

Transcription and nuclear factor-κB

Nuclear factor-κB (NF-κB) is a key regulator in the initiation and progression of IAs by inducing inflammatory genes related to macrophage recruitment,[23] endothelial dysfunction (vascular cell adhesion protein (VCAM)-1[24] and monocyte chemoattractant protein (MCP)-1[25]), and endothelial cell membrane (ECM) degradation (through interleukin [IL]-1β-mediated down-regulation of procollagen genes).[26] In the intima and media of IA walls, NF-κB (nuclear factor kappa-light chain-enhancer of activated B cells) is activated in the initial stage of aneurysm formation, and is significantly upregulated in ruptured IAs compared with the unruptured ones.[27] In murine animal models, NF-κB knock-down inhibits IA formation and macrophage infiltration,[28] and treatment by NF-κB chimeric decoy oligodeoxynucleotide (ODN) diminishes the volume and thickens the wall of induced IAs [29] [Table 1].

Mitogen-activated protein kinases

Mitogen-activated protein kinases (MAPKs) are a family of intracellular signaling proteins consisting of JNKs, p38 MAPKs, and extracellular signal-regulated kinases (ERKs). JNK participates in the growth and rupture of IAs, and p38 is associated with the formation of IA.[11] Both the phosphorylated JNK and its substrate c-Jun levels are significantly elevated in SMCs of the IA walls.[30] JNK and p38 MAPKs can be activated by stresses such as inflammatory stimuli and wall shear stress, both of which are linked to IA pathogenesis, whereas c-Jun promotes SMC proliferation and intimal hyperplasia.[31] In addition, TNF-α, which is one of the activators of JNK and p38 MAPKs, increases in ruptured IAs [Table 1].

 » ANRIL and Its Regulatory Mechanism Top

ANRIL, also called CDKN2B-AS, is a long noncoding RNA (lncRNA) mostly localized in the nucleus, the gene of which is located on Chr9p21.3 spanning 126.3 kb within the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) gene cluster. In 2007, ANRIL was first discovered in whole blood leukocytes and lymphoblastoid cell lines.[31] It originated in placental mammals and evolved to highly conserved forms in simians. No ortholog of human ANRIL is found in mice. ANRIL possesses 20 exons that can be selectively transcribed in the antisense direction, and the full-length mRNA spans 3834 bp. ANRIL is transcribed by RNA polymerase II and can be spliced into more than 20 linear or circular tissue-specific isoforms.[103],[104] It has been discovered that the inflammatory factor (INF)-γ, deoxyribonucleic acid (DNA) damage, and microRNAs regulate ANRIL in a cell-type specific manner.

ANRIL has multiple isoforms. Next generation DNA sequencing indicates that the expression level of each exon is different.[103],[104] The function of ANRIL is not based on the full length of the transcript; its conserved stem-loop structure can be recognized and bound by polycomb proteins, and the isoform containing such a structure can be an independent regulator.[105] Polycomb group complexes are epigenetic regulatory complexes that conduct transcriptional repression of target genes via modifying the chromatin. ANRIL can specifically bind to subunits of polycomb proteins to silence CDKN2A/B. ANRIL can also silence CDKN2B through pathways dependent on Dicer, a key part in RNA interference.[106],[107] Moreover, ANRIL has targets other than CDKN2A/B such as CARD8 and KLF2.[108],[109]

The CDKN2A/B locus contains three important tumor suppression genes, namely, CDKN2A, CDKN2B, and S-methyl-5'-thioadenosine phosphorylase (MTAP). Genomic-wide association studies (GWAS) show that single nucleotide polymorphisms (SNPs) in ANRIL links to a variety of tumors, and CDKN2A/B is comprehensively silenced in tumorigenesis.[110]In vivo and in vitro studies have shown that ANRIL deficiency or silence relates to a low proliferation level of cells,[111],[112] which is an important mechanism responsible for preventing tumorigenesis. Furthermore, ANRIL is the primary candidate gene of atherosclerosis at the 9p21 locus, although whether it plays a promoting or an inhibiting role is controversial.[111] Studies show that ANRIL is the genetic susceptible locus for coronary heart disease, abdominal aortic aneurysm (AAA), and ischemic stroke.[113] The human coronary artery disease-associated SNPs are located within a 58 kb linkage disequilibrium block on chromosome 9p21.3 that overlaps the 3′ end of ANRIL gene. The association between ANRIL and cardiovascular diseases is independent of most of the traditional risk factors; therefore, it may represent an unknown etiology.

 » Discovery of Links between ANRIL And Intracranial Aneurysms Top

The linkage between ANRIL and IAs has been proved in a series of GWAS. In 2008, Bilguvar et al.,[114] first discovered that three SNPs (rs1333040, rs10116277, rs2383207) in the ANRIL gene were significantly associated with IAs. The combined effects of the three loci showed a more than threefold increase than the effect of a single locus. The same team further proved the association in an expanded sample several years later. Foroud et al.,[115] conducted a study on IAs with and without family history, and their meta-analysis indicated that the most significantly associated SNP was in ANRIL (rs6475606). Later, an expanded study proved that the SNP in ANRIL (rs10733376) represented the factor that had the most significant relevance with IAs.[116] Low et al.,[117] found that rs10757278 in ANRIL was significantly associated with IAs, and confirmed the role of rs1333040. In 2013, Alg et al., reviewed the reported GWAS studies and discovered that rs10757278 and rs1333040 in ANRIL showed the strongest associations among the genomes.[118] Notably, studies indicated that the association between these SNPs and IA was independent of hypertension [119] and smoking.[120] It had the strongest association with the posterior communicating artery IAs, suggesting the genetic influence on the anatomical position of IA.[120]

Possible pathway of ANRIL leading to intracranial aneurysm formation

Cyclin-dependent kinase inhibitor 2A/B [Figure 1]
Figure 1: A diagram showing the molecular mechanism of ANRIL in IA pathogenesis (SMC, smooth muscle cell; MAC, macrophage; BMDC, bone marrow-derived cell; FIB, fibroblast; CARD8: caspase recruitment domain 8; KLF2: Krüppel-like factor 2; ANRIL: Antisense noncoding RNA in the INK4 locus)

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Human CDKN2A/B gene cluster is located on chromosome 9. CDKN2A selectively transcribes two different proteins p16INK4a and p14ARF through an open reading frame, and CDKN2B transcribes p15INK4b. Both p16INK4a and p15INK4b are cyclin dependent kinase (CDK) inhibitors that contain multiple ankyrin repeat domains that allow them to bind to CDK4 and CDK6, thereby inhibiting the formation of a complex of these CDKs with cyclins. This inhibition blocks the hyper-phosphorylation of the retinoblastoma protein and the subsequent activation of the transcription factor E2F, which induces the transcription of genes controlling cell cycle progression. p14ARF Human variant/p19ARF mouse variant also functions as a cell cycle inhibitor by affecting the p53 pathway. ANRIL regulates CDKN2A/B in a cell-type specific mode.In vitro studies showed that interference with ANRIL expression causes a marked increase in CDKN2A and CDKN2B expression in human fibroblasts. Conversely, ANRIL knockdown in structural maintenance of chromosomes family proteins reduces both CDKN2A levels and cell growth, whereas it increases CDKN2B expression.[111] Cell cycle regulation has been shown to be an essential mechanism in the cardiovascular disease development.

The cerebral vessels lack an external elastic lamina, making them more vulnerable to hemodynamic shear stresses. The decreased number of SMCs contributes to an abnormal contractibility and a stiffer nature of arteries, that acts as a predisposing factor to outpouching in high pressure areas. Apoptosis of SMCs in the wall of IA was discovered using single stranded DNA (ssDNA) immunohistochemistry,[121] and it is involved in the genesis of SAH.[122] Loss of CDKN2B promotes p53-dependent SMC apoptosis and abdominal aortic aneurysm (AAA) formation,[123] independent of changes in inflammatory immune cells. Increased p16INK4a expression mediates the inhibition of SMC proliferation by peroxisome proliferator-activated receptor (PPAR) α, and p16INK4a deficiency enhances SMC proliferation and intimal hyperplasia in a carotid arterial-injury mouse model.[124] The expression of CDKN2A is downregulated in ruptured IAs than in unruptured IAs.[125] On the other hand, the phenotype of SMCs in IA walls, which partially changes to the synthetic type, is different from the contractile type in the media of normal cerebral arteries. Silencing of ANRIL reduces the proliferation of vascular SMCs,[110] which might be the result of premature senescence, an important mechanism in endothelial dysfunction [126] and the SMC conversion to a proinflammatory phenotype.

Cell cycle inhibitors may also protect against IAs by controlling macrophage proliferation. It is demonstrated that p16INK4a deficiency in macrophages decreases their inflammatory potential by diminishing signal transducer and activator of transcription 1 (STAT1) and nuclear factor (NF)-κB signaling, leading to a phenotype resembling alternatively polarized macrophages.[127] In atherosclerotic lesions, p16INK4a localizes to a subset of cluster of differentiation (CD) 68-positive macrophages and positively correlates with tumor necrosis factor (TNF)-α, which promotes the formation of IAs.[128]

IAs are predominately located at places that incur endothelial damage. Vascular injury mobilizes bone marrow-derived cells (BMDCs) that localize to these sites and contribute to repair. p16INK4a has a role in the regulation of BMDC populations,[129] and defective vascular repair may cause IAs. Proliferation of fibroblasts that protect against IAs is also reduced by silencing of ANRIL.[112]

Krüppel-like Factor 2 [Figure 1]

Krüppel-like factor(KLF) family transcription factors contain Cys2/His zinc finger domains, and can act as inhibitors or stimulators while taking part in cell differentiation and proliferation in a promoter-dependent manner.[130] Lung Krüppel-like factor (LKLF)−/− is present in embryos of mice that have disrupted angiogenesis and vasculogenesis and have displayed aneurysmal dilatation because of lack of SMC recruitment and tunica media formation.[131] In ruptured IAs, the expression of KLFs is downregulated compared with their expression in unruptured IAs.[125] In a study of lung cancer [132] and hepatocellular carcinoma,[133] it was found that partially mediated by p21, ANRIL recruits polycomb repressive complex (2PRC2) and inhibits the expression of KLF2. This signaling pathway is independent of the epigenetic regulation of p15.

The endothelium forms the inner lining of all blood vessels and regulates the vascular barrier function, blood coagulation, and homing of immune cells. KLF2 regulates EC function and vascular homeostasis.[134] KLF2 could be induced by shear stress to make ECs anti-inflammatory.[134] Propermeability factors such as inflammatory stimuli (e.g., lipopolysaccharide or TNF-α) promote paracellular vascular leak through the disruption of the cell–cell junctions between ECs or due to cytoskeletal contraction.[135] These two disruption mechanisms share the phosphorylation of endothelial myosin light chain as a common downstream pathway. KLF2 inhibits both mechanisms by preventing this phosphorylation process.[136] Tight junctions (TJs) and adherens junctions play key roles in the maintenance of the endothelial barrier, and TJs are abundant in blood–brain barrier.[137] KLF2 could selectively induce the expression of TJ protein occluding properties.[136]

KLF2 plays an anti-inflammatory role in multiple cell types. In monocytes, KLF2 inhibits NF-κB.[138] One mechanism that it adopts is by competing with NF-κB in binding CBP/p300, a coactivator of transcription. Thus, KLF2 reduces NF-κB dependent transcriptional activity and the expression of targeted genes (such as vascular cell adhesion molecule 1 [VCAM-1]).[139] The other mechanism by which it acts is by inhibiting proteolytic activation receptor 1 (PAR-1). Thus, KLF2 decreases nuclear aggregation and the subsequent DNA binding of NF-κB.[140] Macrophages possess two subtypes, the proinflammatory type M1 and the anti-inflammatory type M2. Expression of KLF2 in M2 is higher than in M1, and its knockdown in M2 leads to an increased secretion of monocyte chemoattractant protein-1 (MCP-1).[141] The overexpression of KLF2 in human umbilical vein endothelial cell prohibits IL-1β, TNF-α, and VCAM-1, leading to reduced adherence and rolling of immune cells to the endothelium.[142] Furthermore, KFL2 can inhibit the c-Jun N-terminal kinase(JNK) pathway by modifying the actin cytoskeleton,[143] and can prohibit the TGF-β signaling [144] through Smad activation or activating protein 1(AP-1).

Angiogenesis within the aneurysm wall is considered to regulate aneurysm wall remodeling and is suspected to have a critical role in aneurysm formation and rupture.[12] Stromal cell-derived factor-1 (SDF-1), a chemokine with a robust role in angiogenesis and in the activation of the inflammatory cascade, has been suggested to have a role in the development of intracranial aneurysms, and blockade of SDF-1 decreased the incidence of developing IAs.[145] KLF2 has potent anti-angiogenic effects. Its overexpression inhibits VEGF, which mediates angiogenesis through EC stimulation and metastasis. Endothelial progenitor cells (EPCs) are bone marrow-derived cells, which take part in angiogenesis. Overexpression of KLF2 in EPCs improves the neovascularization capacity of aged endothelial progenitor cells (EPCs).[146]

Caspase recruitment domain family, member 8 [Figure 1]

Caspase recruitment domain family, member 8 (CARD8) (also known as TUCAN/CARDINAL) belongs to the CARD-containing family of proteins, which plays a role in pathways leading to activation of caspases and NF-κB. CARD8 is a component of inflammasome, a protein complex that is associated with the activation of proinflammatory caspases. The gene of CARD8 can be alternatively transcribed to different variants. CARD8 functions like an adaptor molecule that suppresses activation of NF-κB, secretion of IL-1β, and apoptosis.[147] CARD8 represses NF-κB through the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) pathway, causing the inhibition of inflammatory reaction. An in vitro study has shown that homozygotes for the stop codon allele T reduce CARD8 expression and its NF-κB-inhibiting attribute.[148]

Previous studies indicate that ANRIL might modulate targeted genes by cis- or trans- acting effects. Transregulation is dependent on arthrobacter luteus (Alu) motifs that mark the promoters of ANRIL target genes and are mirrored in ANRIL RNA transcripts.[104] Bioinformatic analysis of CARD8 shows that the same core Alu motif is also present in the DNA promoter sequence of CARD8. Thus, ANRIL may transregulate CARD8 expression.[108]

The C10X polymorphism (rs 2043211), which is located in the exon 5 of CARD8 gene, is a nonsense mutation leading to a truncated CARD8 protein, and it relates to cardiovascular diseases such as ischemic stroke.[149] Researches show that the presence of polymorphic allele correlated with elevated cell death in vitro, presumably as a result of losing the capacity of suppressing caspase 1 and NF-κB activity.[150] In addition, this variant is related to lower C-reactive protein values and circulating monocyte chemoattractant protein (MCP)-1 levels.[151] This is in accordance with studies revealing that impaired inflammasome activation lowers MCP-1 expression, leading to a reduced inflammatory response.[152]

CARD8 has also been linked to NLRP3 complex, an inflammasome composed of NLRP3 scaffold protein, ASC (PYCARD) adaptor protein, and caspase-1.[153] The polymorphisms Q705K (rs35829419) in NLRP3 gene, combined with C10X, is related to the upregulated levels of plasma IL-1β and IL-33.[154] In addition, the interaction between the gene Q705K and C10X protects against abdominal aortic aneurysms.[155] IL-1β is a crucial proinflammatory factor regulating inflammation in the vessel wall and in promoting atherogenic progression.[156] Inhibition of IL-1β helps in preventing the adverse vascular remodeling process that contributes to aneurysmal initiation.[26]

Since it is expressed in the vessel wall, CARD8 is likely to play a role in regulating the basal active state of inflammatory reaction and thereby participating in the process of IAs.

Retinoid metabolism [Figure 1]

Retinoids possess a crucial role in the regulation of various bioprocesses including vision, bone development, immunity, cell proliferation and differentiation, and anti-oncogene activation. SNP-set (Sequence) Kernel Association Test (SKAT) has been used to identify ANRIL's trans-effected genes.[157] The top five genes are ABCA1, CASP14, EIF1AY, DUT, and DHRS9, which participate in cholesterol efflux, apoptosis, stroke, and DNA replication. DHRS9 encodes an enzyme that is involved in retinol metabolism.[158] Through gene enrichment test, retinol metabolism has been proven to be the top influential pathway, which has a crucial role in the atherogenic process, endothelial function, vascular calcification, and lipid metabolism.[159] It is noteworthy that DHRS9 has two transcriptional variants within the nominally significant transcripts identified by the SKAT test, enhancing the confidence that this gene exhibits a true trans-effect. The two transcriptional variants, namely alcohol dehydrogenase (ADH) and cytochrome P450 26A1 and 26B1 (CYP26B1), are critical enzymes participating in retinoid metabolism in vessels. ADH converts retinol to retinaldehyde, and regulates vascular biology through its controlling of the alcohol metabolism,[160] and it also has direct effects upon abdominal vessels.[161]CYP26B1 is constitutively expressed in human aortic SMCs. By inhibiting all-trans retinoic acid (atRA) signaling, CYP26B1 participates in the biological process of SMCs. All-trans retinoic acid (AtRA) reduces the neointimal area in a common carotid artery balloon injury model of a rat, possibly through downregulated SMC proliferation and differentiation, and upregulated SMC migration at the injured area.[162] At an early stage of vascular impairment, SMCs migrate from the media to the intima where they promote ECM deposition and thicken the vessel wall.[163] It is critical to the arterial response to injury that SMCs change from the contractile phenotype to the synthetic phenotype with inhibited differentiation. Thus, retinoids may be associated with IA by migration and apoptosis of SMCs. Previous work also indicates that retinoids take part in controlling expression of endothelial adhesion molecules, which is an inflammatory process that occurs at an early stage of aneurysmal formation.[164]

β-carotene, consisting of two retinyl groups, is dissociated to retinal (a form of vitamin A) in the small intestine. Angiotensin (Ang) II may induce IAs via the RAS system through decreasing the levels of MMP-2, urinary plasminogen activator ( uPA), PAI, peroxisome proliferator-activated receptors (PPAR)-A, macrophage colony stimulating factor (MCSF) 1 and increasing the levels of tissue plasminogen activator (tPA) and monocyte chemoattractant protein (MCP)-1. β-carotene reduces circulating macrophages and brings to normal the expression levels of the above candidate genes, and therefore, protects against the pathological processes.[80]

Vitamin A (retinol), which is a predominant natural circulating retinoid, is an essential vitamin.[165] The lack of vitamin A leads to impaired immunity, anemia, and mortality. Retinoic acid (RA) is the active metabolite of vitamin A. It upregulates MMPs expression,[166] inhibits chemokine production,[167] and represses VCAM-1 stimulation in ECs.[168] AtRA also induces angiogenesis via retinoic acid receptor by promoting human umbilical vein endothelial cell (HUVEC) proliferation and endogenous VEGF signaling.[169]

 » Summary Top

IA is often a fatal disease, and presently, there are surgical and endovascular options for its treatment. Both the options, however, may be associated with serious therapeutic complications. There are already studies showing that molecular interventions can regress AAAs.[170],[171] Although the pathogenesis of IAs and abdominal aortic aneurysms are different, there are some common pathological mechanisms; macrophage infiltration into the vascular wall, ECM degradation by MMPs, and defect in ECM biological synthesis. Therefore, a medication that regresses IAs may greatly expand our options in treating IAs and may be used alone or in conjunction with the surgical options.

Since its discovery, ANRIL has been strongly linked to multiple cardiovascular diseases, both atherosclerotic and nonatherosclerotic. It is also a biomarker of some tumors. Thus, the mechanisms by which ANRIL affects so many pathologically different diseases is of major concern. There are several ways in which the noncoding RNA ANRIL can alter the expression of associated protein coding genes, which include RNA interference, gene silencing, chromatin remodeling, and DNA methylation.[172] As with IAs, the detailed mechanism of ANRIL has rarely been studied. This article summarizes previous studies and the possible proposed signaling pathways. Research in the future will unequivocally establish the role of ANRIL as a biomarker of IAs or as a therapeutic target in which interference with the ANRIL metabolic pathway may lead to regression of IAs.

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