Atormac
Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 568  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Search
 
  
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (1,085 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

 
  In this Article
 »  Abstract
 »  Molecular Mechan...
 » Summary
 »  ANRIL and...
 »  Discovery of Lin...
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed2247    
    Printed60    
    Emailed0    
    PDF Downloaded44    
    Comments [Add]    

Recommend this journal

 


 
Table of Contents    
REVIEW ARTICLE
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
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/neuroindia.NI_1074_15

Rights and Permissions

 » 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 2019 Dec 7];65:718-28. Available from: http://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

Click here to view


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)

Click here to view


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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Rinkel GJ, Djibuti M, Algra A, van Gijn J. Prevalence and risk of rupture of intracranial aneurysms: A systematic review. Stroke 1998;29:251-6.  Back to cited text no. 1
    
2.
Zacharia BE, Hickman ZL, Grobelny BT, DeRosa P, Kotchetkov I, Ducruet AF, et al. Epidemiology of aneurysmal subarachnoid hemorrhage. Neurosurg Clin N Am 2010;21:221-33.  Back to cited text no. 2
    
3.
Huang J, van Gelder JM. The probability of sudden death from rupture of intracranial aneurysms: A meta-analysis. Neurosurgery 2002;51:1101-5.  Back to cited text no. 3
    
4.
Kissela BM, Sauerbeck L, Woo D, Khoury J, Carrozzella J, Pancioli A, et al. Subarachnoid hemorrhage: A preventable disease with a heritable component. Stroke 2002;33:1321-6.  Back to cited text no. 4
    
5.
Pleizier CM, Ruigrok YM, Rinkel GJ. Relation between age and number of aneurysms in patients with subarachnoid haemorrhage. Cerebrovasc Dis 2002;14:51-3.  Back to cited text no. 5
    
6.
Struycken PM, Pals G, Limburg M, Pronk JC, Wijmenga C, Pearson PL, et al. Anticipation in familial intracranial aneurysms in consecutive generations. Eur J Hum Genet 2003;11:737-43.  Back to cited text no. 6
    
7.
Stehbens WE. Hypertension and cerebral aneurysms. Med J Aust 1962;49:8-10.  Back to cited text no. 7
    
8.
Krex D, Schackert HK, Schackert G. Genesis of cerebral aneurysms–An update. Acta Neurochir 2001;143:429-48.  Back to cited text no. 8
    
9.
Ruigrok YM, Rinkel GJ, Wijmenga C. Genetics of intracranial aneurysms. Lancet Neurol 2005;4:179-89.  Back to cited text no. 9
    
10.
Bruno G, Todor R, Lewis I, Chyatte D. Vascular extracellular matrix remodeling in cerebral aneurysms. J Neurosurg 1998;89:431-40.  Back to cited text no. 10
    
11.
Laaksamo E, Tulamo R, Baumann M, Dashti R, Hernesniemi J, Juvela S, et al. Involvement of mitogen-activated protein kinase signaling in growth and rupture of human intracranial aneurysms. Stroke 2008;39:886-92.  Back to cited text no. 11
    
12.
Kilic T, Sohrabifar M, Kurtkaya O, Yildirim O, Elmaci I, Gunel M, et al. Expression of structural proteins and angiogenic factors in normal arterial and unruptured and ruptured aneurysm walls. Neurosurgery 2005;57:997-1007.  Back to cited text no. 12
    
13.
Frösen J, Piippo A, Paetau A, Kangasniemi M, Niemelä M, Hernesniemi J, et al. Growth factor receptor expression and remodeling of saccular cerebral artery aneurysm walls: Implications for biological therapy preventing rupture. Neurosurgery 2006;58:534-41.  Back to cited text no. 13
    
14.
Wei H, Mao Q, Liu L, Xu Y, Chen J, Jiang R, et al. Changes and function of circulating endothelial progenitor cells in patients with cerebral aneurysm. J Neurosci Res 2011;89:1822-8.  Back to cited text no. 14
    
15.
Yoneyama T, Kasuya H, Onda H, Akagawa H, Jinnai N, Nakajima T, et al. Association of positional and functional candidate genes FGF1, FBN2, and LOX on 5q31 with intracranial aneurysm. J Hum Genet 2003;48:309-14.  Back to cited text no. 15
    
16.
Aoki T, Kataoka H, Ishibashi R, Nozaki K, Egashira K, Hashimoto N. Impact of monocyte chemoattractant protein-1 deficiency on cerebral aneurysm formation. Stroke 2009;40:942-51.  Back to cited text no. 16
    
17.
Gaetani P, Tartara F, Pignatti P, Tancioni F, Rodriguez y Baena R, De Benedetti F. Cisternal CSF levels of cytokines after subarachnoid hemorrhage. Neurol Res 1998;20:337-42.  Back to cited text no. 17
    
18.
Jayaraman T, Paget A, Shin YS, Li X, Mayer J, Chaudhry H, et al. TNF alpha-mediated inflammation in cerebral aneurysms: A potential link to growth and rupture. Vasc Health Risk Manag 2008;4:805-17.  Back to cited text no. 18
    
19.
Ali MS, Starke RM, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, et al. TNF-alpha induces phenotypic modulation in cerebral vascular smooth muscle cells: Implications for cerebral aneurysm pathology. J Cereb Blood Flow Metab 2013;33:1564-73.  Back to cited text no. 19
    
20.
Starke RM, Ali MS, Jabbour PM, Tjoumakaris SI, Gonzalez F, Hasan DM, et al. Cigarette smoke modulates vascular smooth muscle phenotype: Implications for carotid and cerebrovascular disease. PLoS One 2013;8:e71954.  Back to cited text no. 20
    
21.
Kirwan JP, Krishnan RK, Weaver JA, Del Aguila LF, Evans WJ. Human aging is associated with altered TNF-alpha production during hyperglycemia and hyperinsulinemia. Am J Physiol Endocrinol Metab 2001;281:E1137-43.  Back to cited text no. 21
    
22.
Kondo S, Hashimoto N, Kikuchi H, Hazama F, Nagata I, Kataoka H. Apoptosis of medial smooth muscle cells in the development of saccular cerebral aneurysms in rats. Stroke 1998;29:181-8.  Back to cited text no. 22
    
23.
Aoki T, Kataoka H, Shimamura M, Nakagami H, Wakayama K, Moriwaki T, et al. NF-kappaB is a key mediator of cerebral aneurysm formation. Circulation 2007;116:2830-40.  Back to cited text no. 23
    
24.
Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J 1995;9:899-909.  Back to cited text no. 24
    
25.
Goebeler M, Gillitzer R, Kilian K, Utzel K, Bröcker EB, Rapp UR, et al. Multiple signaling pathways regulate NF-kappaB-dependent transcription of the monocyte chemoattractant protein-1 gene in primary endothelial cells. Blood 2001;97:46-55.  Back to cited text no. 25
    
26.
Aoki T, Kataoka H, Ishibashi R, Nozaki K, Morishita R, Hashimoto N. Reduced collagen biosynthesis is the hallmark of cerebral aneurysm: Contribution of interleukin-1beta and nuclear factor-kappaB. Arterioscler Thromb Vasc Biol 2009;29:1080-6.  Back to cited text no. 26
    
27.
Kurki MI, Häkkinen SK, Frösen J, Tulamo R, von und zu Fraunberg M, Wong G, et al. Upregulated signaling pathways in ruptured human saccular intracranial aneurysm wall: An emerging regulative role of Toll-like receptor signaling and nuclear factor-κm, hypoxia-inducible factor-1A, and ETS transcription factors. Blood 2;68:1667-75.  Back to cited text no. 27
    
28.
Aoki T, Kataoka H, Shimamura M, Nakagami H, Wakayama K, Moriwaki T, et al. NF-kappaB is a key mediator of cerebral aneurysm formation. Circulation 2007;116:2830-40.  Back to cited text no. 28
    
29.
Aoki T, Kataoka H, Nishimura M, Ishibashi R, Morishita R, Miyamoto S. Regression of intracranial aneurysms by simultaneous inhibition of nuclear factor-κa and Ets with chimeric decoy oligodeoxynucleotide treatment. Neurosurgery. 2012;70:1534-43  Back to cited text no. 29
    
30.
Takagi Y, Ishikawa M, Nozaki K, Yoshimura S, Hashimoto N. Increased expression of phosphorylated c-Jun amino-terminal kinase and phosphorylated c-Jun in human cerebral aneurysms: Role of the c-Jun amino-terminal kinase/c-Jun pathway in apoptosis of vascular walls. Neurosurgery 2002;51:997-1002.  Back to cited text no. 30
    
31.
Yasumoto H, Kim S, Zhan Y, Miyazaki H, Hoshiga M, Kaneda Y, et al. Dominant negative c-Jun gene transfer inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia in rats. Gene Ther 2001;8:1682-9.  Back to cited text no. 31
    
32.
Zhu YQ, Li MH, Yan L, Tan HQ, Cheng YS. Arterial wall degeneration plus hemodynamic insult cause arterial wall remodeling and nascent aneurysm formation at specific sites in dogs. J Neuropathol Exp Neurol 2014;73:808-19.  Back to cited text no. 32
    
33.
Liaw N, Fox JM, Siddiqui AH, Meng H, Kolega J. Endothelial nitric oxide synthase and superoxide mediate hemodynamic initiation of intracranial aneurysms. PLoS One 2014;9:e101721.  Back to cited text no. 33
    
34.
Wang J, Tan HQ, Zhu YQ, Li MH, Li ZZ, Yan L, et al. Complex hemodynamic insult in combination with wall degeneration at the apex of an arterial bifurcation contributes to generation of nascent aneurysms in a canine model. AJNR Am J Neuroradiol 2014;35:1805-12.  Back to cited text no. 34
    
35.
Yokoi T, Isono T, Saitoh M, Yoshimura Y, Nozaki K. Suppression of cerebral aneurysm formation in rats by a tumor necrosis factor-α inhibitor. J Neurosurg 2014;120:1193-200.  Back to cited text no. 35
    
36.
Mandelbaum M, Kolega J, Dolan JM, Siddiqui AH, Meng H. A critical role for proinflammatory behavior of smooth muscle cells in hemodynamic initiation of intracranial aneurysm. PLoS One 201;8:e74357.  Back to cited text no. 36
    
37.
Yan T, Chopp M, Ning R, Zacharek A, Roberts C, Chen J. Intracranial aneurysm formation in type-one diabetes rats. PLoS One 2013;8:e67949.  Back to cited text no. 37
    
38.
Ishibashi R, Aoki T, Nishimura M, Miyamoto S. Imidapril inhibits cerebral aneurysm formation in an angiotensin-converting enzyme-independent and matrix metalloproteinase-9-dependent manner. Neurosurgery 2012;70:722-30.  Back to cited text no. 38
    
39.
Kolega J, Gao L, Mandelbaum M, Mocco J, Siddiqui AH, Natarajan SK, et al. Cellular and molecular responses of the basilar terminus to hemodynamics during intracranial aneurysm initiation in a rabbit model. J Vasc Res 2011;48:429-42.  Back to cited text no. 39
    
40.
Xu Y, Tian Y, Wei HJ, Dong JF, Zhang JN. Methionine diet-induced hyperhomocysteinemia accelerates cerebral aneurysm formation in rats. Neurosci Lett 2011;494:139-44.  Back to cited text no. 40
    
41.
Xu Y, Tian Y, Wei HJ, Chen J, Dong JF, Zacharek A, et al. Erythropoietin increases circulating endothelial progenitor cells and reduces the formation and progression of cerebral aneurysm in rats. Neuroscience 2011;181:292-9.  Back to cited text no. 41
    
42.
Yagi K, Tada Y, Kitazato KT, Tamura T, Satomi J, Nagahiro S. Ibudilast inhibits cerebral aneurysms by down-regulating inflammation-related molecules in the vascular wall of rats. Neurosurgery 2010;66:551-9.  Back to cited text no. 42
    
43.
Nuki Y, Tsou TL, Kurihara C, Kanematsu M, Kanematsu Y, Hashimoto T. Elastase-induced intracranial aneurysms in hypertensive mice. Hypertension 2009;54:1337-44.  Back to cited text no. 43
    
44.
Tada Y, Kitazato KT, Tamura T, Yagi K, Shimada K, Kinouchi T, et al. Role of mineralocorticoid receptor on experimental cerebral aneurysms in rats. Hypertension 2009;54:552-7.  Back to cited text no. 44
    
45.
Wang Z, Kolega J, Hoi Y, Gao L, Swartz DD, Levy EI, et al. Molecular alterations associated with aneurysmal remodeling are localized in the high hemodynamic stress region of a created carotid bifurcation. Neurosurgery 2009;65:169-77.  Back to cited text no. 45
    
46.
Aoki T, Kataoka H, Ishibashi R, Nakagami H, Nozaki K, Morishita R, et al. Pitavastatin suppresses formation and progression of cerebral aneurysms through inhibition of the nuclear factor kappa B pathway. Neurosurgery 2009;64:357-65.  Back to cited text no. 46
    
47.
Jamous MA, Nagahiro S, Kitazato KT, Tamura T, Aziz HA, Shono M, et al. Endothelial injury and inflammatory response induced by hemodynamic changes preceding intracranial aneurysm formation: Experimental study in rats. J Neurosurg 2007;107:405-11.  Back to cited text no. 47
    
48.
Pannu H, Kim DH, Guo D, King TM, Van Ginhoven G, Chin T, et al. The role of MMP-2 and MMP-9 polymorphisms in sporadic intracranial aneurysms. J Neurosurg 2006;105:418-23.  Back to cited text no. 48
    
49.
Peters DG, Kassam A, St Jean PL, Yonas H, Ferrell RE. Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysm. Stroke 1999;30:2612-6.  Back to cited text no. 49
    
50.
Caird J, Napoli C, Taggart C, Farrell M, Bouchier-Hayes D. Matrix metalloproteinases 2 and 9 in human atherosclerotic and non-atherosclerotic cerebral aneurysms. Eur J Neurol 2006;13:1098-105.  Back to cited text no. 50
    
51.
Krex D, Kotteck K, König IR, Ziegler A, Schackert HK, Schackert G. Matrix metalloproteinase-9 coding sequence single-nucleotide polymorphisms in Caucasians with intracranial aneurysms. Neurosurgery 2004;55:207-12.  Back to cited text no. 51
    
52.
Szczudlik P, Borratyńska A. Association between the -1562 C/T MMP-9 polymorphism and cerebrovascular disease in a Polish population. Neurol Neurochir Pol 2010;44:350-7.  Back to cited text no. 52
    
53.
Yoon S, Tromp G, Vongpunsawad S, Ronkainen A, Juvonen T, Kuivaniemi H. Genetic analysis of MMP3, MMP9, and PAI-1 in Finnish patients with abdominal aortic or intracranial aneurysms. Biochem Biophys Res Commun 1999;265:563-8.  Back to cited text no. 53
    
54.
Li B, Li F, Chi L, Zhang L, Zhu S. The expression of SPARC in human intracranial aneurysms and its relationship with MMP-2/-9. PLoS One 2013;8:e58490.  Back to cited text no. 54
    
55.
Takemura Y, Hirata Y, Sakata N, Nabeshima K, Takeshita M, Inoue T. Histopathologic characteristics of a saccular aneurysm arising in the non-branching segment of the distal middle cerebral artery. Pathol Res Pract 2010;206:391-6.  Back to cited text no. 55
    
56.
Saito A, Fujimura M, Inoue T, Shimizu H, Tominaga T. Lectin-like oxidized low-density lipoprotein receptor 1 and matrix metalloproteinase expression in ruptured and unruptured multiple dissections of distal middle cerebral artery: Case report. Acta Neurochir 2010;152:1235-40.  Back to cited text no. 56
    
57.
Aoki T, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N. Simvastatin suppresses the progression of experimentally induced cerebral aneurysms in rats. Stroke 2008;39:1276-85.  Back to cited text no. 57
    
58.
Jin D, Sheng J, Yang X, Gao B. Matrix metalloproteinases and tissue inhibitors of metalloproteinases expression in human cerebral ruptured and unruptured aneurysm. Surg Neurol 2007;68(Suppl 2):S11-6.  Back to cited text no. 58
    
59.
Aoki T, Kataoka H, Moriwaki T, Nozaki K, Hashimoto N. Role of TIMP-1 and TIMP-2 in the progression of cerebral aneurysms. Stroke 2007;38:2337-45.  Back to cited text no. 59
    
60.
Aoki T, Kataoka H, Morimoto M, Nozaki K, Hashimoto N. Macrophage-derived matrix metalloproteinase-2 and -9 promote the progression of cerebral aneurysms in rats. Stroke 2007;38:162-9.  Back to cited text no. 60
    
61.
Kim SC, Singh M, Huang J, Prestigiacomo CJ, Winfree CJ, Solomon RA, et al. Matrix metalloproteinase-9 in cerebral aneurysms. Neurosurgery 1997;41:642-66.  Back to cited text no. 61
    
62.
Li S, Tian Y, Huang X, Zhang Y, Wang D, Wei H, et al. Intravenous transfusion of endothelial colony-forming cells attenuates vascular degeneration after cerebral aneurysm induction. Brain Res 2014;1593:65-75.  Back to cited text no. 62
    
63.
Kadirvel R, Ding YH, Dai D, Zakaria H, Robertson AM, Danielson MA, et al. The influence of hemodynamic forces on biomarkers in the walls of elastase-induced aneurysms in rabbits. Neuroradiology 2007;49:1041-53.  Back to cited text no. 63
    
64.
Peña Silva RA, Kung DK, Mitchell IJ, Alenina N, Bader M, Santos RA, et al. Angiotensin 1-7 reduces mortality and rupture of intracranial aneurysms in mice. Hypertension 2014;64:362-8.  Back to cited text no. 64
    
65.
Marchese E, Vignati A, Albanese A, Nucci CG, Sabatino G, Tirpakova B, et al. Comparative evaluation of genome-wide gene expression profiles in ruptured and unruptured human intracranial aneurysms. J Biol Regul Homeost Agents 2010;24:185-95.  Back to cited text no. 65
    
66.
Zhang B, Dhillon S, Geary I, Howell WM, Iannotti F, Day IN, et al. Polymorphisms in matrix metalloproteinase-1, -3, -9, and -12 genes in relation to subarachnoid hemorrhage. Stroke 2001;32:2198-202.  Back to cited text no. 66
    
67.
Cheng WT, Wang N. Correlation between MMP-2 and NF-κ B expression of intracranial aneurysm. Asian Pac J Trop Med 2013;6:570-3.  Back to cited text no. 67
    
68.
Low SK, Zembutsu H, Takahashi A, Kamatani N, Cha PC, Hosono N, et al. Impact of LIMK1, MMP2 and TNF-α variations for intracranial aneurysm in Japanese population. J Hum Genet 2011;56:211-6.  Back to cited text no. 68
    
69.
Aoki T, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N. Nifedipine inhibits the progression of an experimentally induced cerebral aneurysm in rats with associated down-regulation of NF-kappa B transcriptional activity. Curr Neurovasc Res 2008;5:37-45.  Back to cited text no. 69
    
70.
Todor DR, Lewis I, Bruno G, Chyatte D. Identification of a serum gelatinase associated with the occurrence of cerebral aneurysms as pro-matrix metalloproteinase-2. Stroke 1998;29:1580-3.  Back to cited text no. 70
    
71.
Santiago-Sim T, Mathew-Joseph S, Pannu H, Milewicz DM, Seidman CE, Seidman JG, et al. Sequencing of TGF-beta pathway genes in familial cases of intracranial aneurysm. Stroke 2009;40:1604-11.  Back to cited text no. 71
    
72.
Ruigrok YM, Baas AF, Medic J, Wijmenga C, Rinkel GJ. The transforming growth factor-β receptor genes and the risk of intracranial aneurysms. Int J Stroke 2012;7:645-8.  Back to cited text no. 72
    
73.
Ruigrok YM, Tan S, Medic J, Rinkel GJ, Wijmenga C. Genes involved in the transforming growth factor beta signaling pathway and the risk of intracranial aneurysms. J Neurol Neurosurg Psychiatry 2008;79:722-4.  Back to cited text no. 73
    
74.
Maderna E, Corsini E, Franzini A, Giombini S, Pollo B, Broggi G, et al. Expression of vascular endothelial growth factor receptor-1/-2 and nitric oxide in unruptured intracranial aneurysms. Neurol Sci 2010;31:617-23.  Back to cited text no. 74
    
75.
Sandalcioglu IE, Wende D, Eggert A, Regel JP, Stolke D, Wiedemayer H. VEGF plasma levels in non-ruptured intracranial aneurysms. Neurosurg Rev 2006;29:26-9.  Back to cited text no. 75
    
76.
Fontanella M, Gallone S, Panciani PP, Garbossa D, Stefini R, Latronico N, et al. Vascular endothelial growth factor gene polymorphisms and intracranial aneurysms. Acta Neurochir 2013;155:1511-5.  Back to cited text no. 76
    
77.
Matsumoto H, Terada T, Tsuura M, Itakura T, Ogawa A. Basic fibroblast growth factor released from a platinum coil with a polyvinyl alcohol core enhances cellular proliferation and vascular wall thickness: An in vitro and in vivo study. Neurosurgery 2003;53:402-7.  Back to cited text no. 77
    
78.
Futami K, Yamashita J, Tachibana O, Kida S, Higashi S, Ikeda K, et al. Basic fibroblast growth factor may repair experimental cerebral aneurysms in rats. Stroke 1995;26:1649-54.  Back to cited text no. 78
    
79.
Aoki T, Fukuda M, Nishimura M, Nozaki K, Narumiya S. Critical role of TNF-alpha-TNFR1 signaling in intracranial aneurysm formation. Acta Neuropathol Commun 2014;2:34.  Back to cited text no. 79
    
80.
Gopal K, Nagarajan P, Raj TA, Jahan P, Ganapathy HS, Mahesh Kumar MJ. Effect of dietary β carotene on cerebral aneurysm and subarachnoid haemorrhage in the brain apo E-/- mice. J Thromb Thrombolysis 2011;32:343-55.  Back to cited text no. 80
    
81.
Kanematsu Y, Kanematsu M, Kurihara C, Tada Y, Tsou TL, van Rooijen N, et al. Critical roles of macrophages in the formation of intracranial aneurysm. Stroke 2011;42:173-8.  Back to cited text no. 81
    
82.
Tada Y, Yagi K, Kitazato KT, Tamura T, Kinouchi T, Shimada K, et al. Reduction of endothelial tight junction proteins is related to cerebral aneurysm formation in rats. J Hypertens 2010;28:1883-91.  Back to cited text no. 82
    
83.
Zhang HF, Zhao MG, Liang GB, Song ZQ, Li ZQ. Expression of pro-inflammatory cytokines and the risk of intracranial aneurysm. Inflammation 2013;36:1195-200.  Back to cited text no. 83
    
84.
Aoki T, Kataoka H, Nishimura M, Ishibashi R, Morishita R, Miyamoto S. Ets-1 promotes the progression of cerebral aneurysm by inducing the expression of MCP-1 in vascular smooth muscle cells. Gene Ther 2010;17:1117-23.  Back to cited text no. 84
    
85.
Ishibashi R, Aoki T, Nishimura M, Hashimoto N, Miyamoto S. Contribution of mast cells to cerebral aneurysm formation. Curr Neurovasc Res 2010;7:113-24.  Back to cited text no. 85
    
86.
Cao Y, Zhao J, Wang S, Zhong H, Wu B. Monocyte chemoattractant protein-1 mRNA in human intracranial aneurysm walls. Zhonghua Yu Fang Yi Xue Za Zhi 2002;36:519-21.  Back to cited text no. 86
    
87.
Komotar RJ, Starke RM, Connolly ES. Endovascular therapy with MCP-1 releasing coils promotes inflammatory intra-aneurysmal tissue healing. Neurosurgery 2012;71:N10-1.  Back to cited text no. 87
    
88.
Starke RM, Chalouhi N, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, et al. Critical role of TNF-α in cerebral aneurysm formation and progression to rupture. J Neuroinflammation 2014;11:77.  Back to cited text no. 88
    
89.
Zhang HF, Zhao MG, Liang GB, Yu CY, He W, Li ZQ, et al. Dysregulation of CD4(+) T cell subsets in intracranial aneurysm. DNA Cell Biol 2016;35:96-103.  Back to cited text no. 89
    
90.
Zhang HF, Zhao MG, Liang GB, Yu CY, Li ZQ, Gao X. Downregulation of T cell immunoglobulin and mucin protein 3 in the pathogenesis of intracranial aneurysm. Inflammation 2015;38:368-74.  Back to cited text no. 90
    
91.
Jayaraman T, Paget A, Shin YS, Li X, Mayer J, Chaudhry H, et al. TNF-alpha-mediated inflammation in cerebral aneurysms: A potential link to growth and rupture. Vasc Health Risk Manag 2008;4:805-17.  Back to cited text no. 91
    
92.
Witkowska AM, Borawska MH, Socha K, Kochanowicz J, Mariak Z, Konopka M. TNF-alpha and sICAM-1 in intracranial aneurismal rupture. Arch Immunol Ther Exp 2009;57:137-40.  Back to cited text no. 92
    
93.
Fontanella M, Rainero I, Gallone S, Rubino E, Fenoglio P, Valfrè W, et al. Tumor necrosis factor-alpha gene and cerebral aneurysms. Neurosurgery 2007;60:668-72.  Back to cited text no. 93
    
94.
Fukuda M, Aoki T. Molecular basis for intracranial aneurysm formation. Acta Neurochir 2015;120:13-5.70.  Back to cited text no. 94
    
95.
Aoki T, Nishimura M, Matsuoka T, Yamamoto K, Furuyashiki T, Kataoka H, et al. PGE(2) -EP(2) signalling in endothelium is activated by haemodynamic stress and induces cerebral aneurysm through an amplifying loop via NF-κB. Br J Pharmacol 2011;163:1237-49.  Back to cited text no. 95
    
96.
Sima X, Xu J, Li J, You C. Association between NFKB1 -94 insertion/deletion ATTG polymorphism and risk of intracranial aneurysm. Genet Test Mol Biomarkers 2013;17:620-4.  Back to cited text no. 96
    
97.
Aoki T, Nishimura M. Targeting chronic inflammation in cerebral aneurysms: Focusing on NF-kappaB as a putative target of medical therapy. Expert Opin Ther Targets 2010;14:265-73.  Back to cited text no. 97
    
98.
Aoki T, Nishimura M, Ishibashi R, Kataoka H, Takagi Y, Hashimoto N. Toll-like receptor 4 expression during cerebral aneurysm formation. Laboratory investigation. J Neurosurg 2010;113:851-8.  Back to cited text no. 98
    
99.
Aoki T, Nishimura M, Kataoka H, Ishibashi R, Miyake T, Takagi Y, et al. Role of angiotensin II type 1 receptor in cerebral aneurysm formation in rats. Int J Mol Med 2009;24:353-9.  Back to cited text no. 99
    
100.
Aoki T, Kataoka H, Shimamura M, Nakagami H, Wakayama K, Moriwaki T, et al. NF-kappa B is a key mediator of cerebral aneurysm formation. Circulation 2007;116:2830-40.  Back to cited text no. 100
    
101.
Kataoka H. Molecular mechanisms of the formation and progression of intracranial aneurysms. Neurol Med Chir 2015;55:214-29.  Back to cited text no. 101
    
102.
Laaksamo E, Ramachandran M, Frösen J, Tulamo R, Baumann M, Friedlander RM, et al. Intracellular signaling pathways and size, shape, and rupture history of human intracranial aneurysms. Neurosurgery 2012;70:1565-72.  Back to cited text no. 102
    
103.
Burd CE, Jeck WR, Liu Y, Sanoff HK, Wang Z, Sharpless NE. Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLoS Genet 2010;6:e1001233.  Back to cited text no. 103
    
104.
Holdt LM, Hoffmann S, Sass K, Langenberger D, Scholz M, Krohn K, et al. Alu elements in ANRIL non-coding RNA at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks. PLoS Genet 2013;9:e1003588.  Back to cited text no. 104
    
105.
Guil S, Soler M, Portela A, Carrère J, Fonalleras E, Gómez A, et al. Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nat Struct Mol Biol 2012;19:664-70.  Back to cited text no. 105
    
106.
Lee YS, Nakahara K, Pham JW, Kim K, He Z, Sontheimer EJ, et al. Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 2004;117:69-81.  Back to cited text no. 106
    
107.
Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, et al. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 2008;451:202-6.  Back to cited text no. 107
    
108.
Bai Y, Nie S, Jiang G, Zhou Y, Zhou M, Zhao Y, Li S, et al. Regulation of CARD8 expression by ANRIL and association of CARD8 single nucleotide polymorphism rs2043211 (p.C10X) with ischemic stroke. Stroke 2014;45:383-8.  Back to cited text no. 108
    
109.
Nie FQ, Sun M, Yang JS, Xie M, Xu TP, Xia R, et al. Long non-coding RNA ANRIL promotes non-small cell lung cancer cells proliferation and inhibits apoptosis by silencing KLF2 and P21 expression. Mol Cancer Ther 2015; 14:268-77.  Back to cited text no. 109
    
110.
Bei JX, Li Y, Jia WH, Feng BJ, Zhou G, Chen LZ, et al. A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nat Genet 2010;42:599-603.  Back to cited text no. 110
    
111.
Congrains A, Kamide K, Oguro R, Yasuda O, Miyata K, Yamamoto E, et al. Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B. Atherosclerosis 2012;220:449-55.  Back to cited text no. 111
    
112.
Muñoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell 2010;38:662-74.  Back to cited text no. 112
    
113.
Cunnington MS, Santibanez Koref M, Mayosi BM, Burn J, Keavney B. Chromosome 9p21 SNPs associated with multiple disease phenotypes correlate with ANRIL expression. PLoS Genet 2010;6:e1000899.  Back to cited text no. 113
    
114.
Bilguvar K, Yasuno K, Niemelref M, Uigrok YM, von Und Zu Fraunberg M, van Duijn CM, et al. Susceptibility loci for intracranial aneurysm in European and Japanese populations. Nat Genet 2008;40:1472-7.  Back to cited text no. 114
    
115.
Foroud T, Koller DL, Lai D, Sauerbeck L, Anderson C, Ko N, et al. Genome-wide association study of intracranial aneurysms confirms role of Anril and SOX17 in disease risk. Stroke 2012;43:2846-52.  Back to cited text no. 115
    
116.
Foroud T, Lai D, Koller D, Van't Hof F, Kurki MI, Anderson CS, et al. Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7. Stroke 2014;45:3194-9.  Back to cited text no. 116
    
117.
Low SK, Takahashi A, Cha PC, Zembutsu H, Kamatani N, Kubo M, et al. Genome-wide association study for intracranial aneurysm in the Japanese population identifies three candidate susceptible loci and a functional genetic variant at EDNRA. Hum Mol Genet 2012;21:2102-10.  Back to cited text no. 117
    
118.
Alg VS, Sofat R, Houlden H, Werring DJ. Genetic risk factors for intracranial aneurysms: A meta-analysis in more than 116,000 individuals. Neurology 2013;80:2154-65.  Back to cited text no. 118
    
119.
Low SK, Takahashi A, Cha PC, Zembutsu H, Kamatani N, Kubo M, et al. Genome-wide association study for intracranial aneurysm in the Japanese population identifies three candidate susceptible loci and a functional genetic variant at EDNRA. Hum Mol Genet 2012;21:2102-10.  Back to cited text no. 119
    
120.
Nakaoka H, Takahashi T, Akiyama K, Cui T, Tajima A, Krischek B, et al. Differential effects of chromosome 9p21 variation on subphenotypes of intracranial aneurysm: Site distribution. Stroke 2010;41:1593-8.  Back to cited text no. 120
    
121.
Sakaki T, Kohmura E, Kishiguchi T, Yuguchi T, Yamashita T, Hayakawa T. Loss and apoptosis of smooth muscle cells in intracranial aneurysms. Studies with in situ DNA end labeling and antibody against single-stranded DNA. Acta Neurochir 1997;139:469-74.  Back to cited text no. 121
    
122.
Pentimalli L, Modesti A, Vignati A, Marchese E, Albanese A, Di Rocco F, et al. Role of apoptosis in intracranial aneurysm rupture. J Neurosurg 2004;101:1018-25.  Back to cited text no. 122
    
123.
Leeper NJ, Raiesdana A, Kojima Y, Kundu RK, Cheng H, Maegdefessel L, et al. Loss of CDKN2B promotes p53-dependent smooth muscle cell apoptosis and aneurysm formation. Arterioscler Thromb Vasc Biol 2013;33:e1-e10.  Back to cited text no. 123
    
124.
Gizard F, Amant C, Barbier O, Bellosta S, Robillard R, Percevault F, et al. PPAR alpha inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a. J Clin Invest 2005;115:3228-38.  Back to cited text no. 124
    
125.
Nakaoka H, Tajima A, Yoneyama T, Hosomichi K, Kasuya H, Mizutani T, et al. Gene expression profiling reveals distinct molecular signatures associated with the rupture of intracranial aneurysm. Stroke 2014;45:2239-45.  Back to cited text no. 125
    
126.
Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I. Endothelial cell senescence in human atherosclerosis: Role of telomere in endothelial dysfunction. Circulation 2002;105:1541-4.  Back to cited text no. 126
    
127.
Cudejko C, Wouters K, Fuentes L, Hannou SA, Paquet C, Bantubungi K, et al. p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages. Blood 2011;118:2556-66.  Back to cited text no. 127
    
128.
Holdt LM, Sass K, Gäbel G, Bergert H, Thiery J, Teupser D. Expression ofChr9p21 genes CDKN2B (p15(INK4b)), CDKN2A (p16(INK4a), p14(ARF)) and MTAP in human atherosclerotic plaque. Atherosclerosis 2011;214:264-70.  Back to cited text no. 128
    
129.
Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 2006;443:421-6.  Back to cited text no. 129
    
130.
Kaczynski J, Cook T, Urrutia R. Sp1- and Krüppel-like transcription factors. Genome Biol 2003;4:206.  Back to cited text no. 130
    
131.
Kuo CT, Veselits ML, Barton KP, Lu MM, Clendenin C, Leiden JM. The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis. Genes Dev 1997;11:2996-3006.  Back to cited text no. 131
    
132.
Nie FQ, Sun M, Yang JS, Xie M, Xu TP, Xia R, et al. Long non-coding RNA ANRIL promotes non-small cell lung cancer cells proliferation and inhibits apoptosis by silencing KLF2 and P21 expression. Mol Cancer Ther 2015;14:268-77.  Back to cited text no. 132
    
133.
Huang MD, Chen WM, Qi FZ, Xia R, Sun M, Xu TP, et al. Long non-coding RNA ANRIL is upregulated in hepatocellular carcinoma and regulates cell apoptosis by epigenetic silencing of KLF2. J Hematol Oncol 2015;8:50.  Back to cited text no. 133
    
134.
Atkins GB, Jain MK. Role of Kruppel-like transcription factors in endothelial biology. Circ Res 2007;100:1686-95.  Back to cited text no. 134
    
135.
Rivero-Vilches FJ, de Frutos S, Saura M, Rodriguez-Puyol D, Rodriguez-Puyol M. Differential relaxing responses to particulate or soluble guanylyl cyclase activation on endothelial cells: A mechanism dependent on PKG-I activation by NO/cGMP. Am J Physiol Cell Physiol 2003; 285:C891-8.  Back to cited text no. 135
    
136.
Lin Z, Natesan V, Shi H, Dong F, Kawanami D, Mahabeleshwar GH, et al. Kruppel-like factor 2 regulates endothelial barrier function. Arterioscler Thromb Vasc Biol 2010;30:1952-9.  Back to cited text no. 136
    
137.
Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD. Blood-brain barrier: Structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol 2006;1:223-36.  Back to cited text no. 137
    
138.
Das H, Kumar A, Lin Z, Patino WD, Hwang PM, Feinberg MW, et al. Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes. Proc Natl Acad Sci USA 2006;103:6653-8.  Back to cited text no. 138
    
139.
SenBanerjee S, Lin Z, Atkins GB, Greif DM, Rao RM, Kumar A, et al. KLF2 is a novel transcriptional regulator of endothelial proinflammatory activation. J Exp Med 2004;199:1305-15.  Back to cited text no. 139
    
140.
Lin Z, Hamik A, Jain R, Kumar A, Jain MK. Kruppel-like factor 2 inhibits protease activated receptor-1 expression and thrombin-mediated endothelial activation. Arterioscler Thromb Vasc Biol 2006;26:1185-9.  Back to cited text no. 140
    
141.
van Tits LJ, Stienstra R, van Lent PL, Netea MG, Joosten LA, Stalenhoef AF. Oxidized LDL enhances pro-inflammatory responses of alternatively activated M2 macrophages: A crucial role for Kruppel-like factor 2. Atherosclerosis 2011;214:345-9.  Back to cited text no. 141
    
142.
Parmar KM, Larman HB, Dai G, Zhang Y, Wang ET, Moorthy SN, et al. Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J Clin Invest 2006;116:49-58.  Back to cited text no. 142
    
143.
Boon RA, Leyen TA, Fontijn RD, Fledderus JO, Baggen JM, Volger OL, et al. KLF2-induced actin shear fibers control both alignment to flow and JNK signaling in vascular endothelium. Blood 2010;115:2533-42.  Back to cited text no. 143
    
144.
Boon RA, Fledderus JO, Volger OL, van Wanrooij EJ, Pardali E, Weesie F, et al. KLF2 suppresses TGF-beta signaling in endothelium through induction of Smad7 and inhibition of AP-1. Arterioscler Thromb Vasc Biol 2007;27:532-9.  Back to cited text no. 144
    
145.
Hoh BL, Hosaka K, Downes DP, Nowicki KW, Wilmer EN, Velat GJ, et al. Stromal cell-derived factor-1 promoted angiogenesis and inflammatory cell infiltration in aneurysm walls. J Neurosurg 2014;120:73-86.  Back to cited text no. 145
    
146.
Boon RA, Urbich C, Fischer A, Fontijn RD, Seeger FH, Koyanagi M, et al. Kruppel-like factor 2 improves neovascularization capacity of aged proangiogenic cells. Eur Heart J 2011;32:371-7.  Back to cited text no. 146
    
147.
Razmara M, Srinivasula SM, Wang L, Poyet JL, Geddes BJ, DiStefano PS, et al. CARD-8 protein, a new CARD family member that regulates caspase-1 activation and apoptosis. J Biol Chem 2002;277:13952-8.  Back to cited text no. 147
    
148.
Bagnall RD, Roberts RG, Mirza MM, Torigoe T, Prescott NJ, Mathew CG. Novel isoforms of the CARD8 (TUCAN) gene evade a nonsense mutation. Eur J Hum Genet 2008;16:619-25.  Back to cited text no. 148
    
149.
Bai Y, Nie S, Jiang G, Zhou Y, Zhou M, Zhao Y, et al. Regulation of CARD8 expression by ANRIL and association of CARD8 single nucleotide polymorphism rs2043211 (p.C10X) with ischemic stroke. Stroke 2014;45:383-8.  Back to cited text no. 149
    
150.
Ko DC, Shukla KP, Fong C, Wasnick M, Brittnacher MJ, Wurfel MM, et al. A genome-wide in vitro bacterial-infection screen reveals human variation in the host response associated with inflammatory disease. Am J Hum Genet 2009;85:214-27.  Back to cited text no. 150
    
151.
Paramel GV, Folkersen L, Strawbridge RJ, Elmabsout AA, Särndahl E, Lundman P, et al. CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation. Clin Sci 2013;125:401-7.  Back to cited text no. 151
    
152.
Stienstra R, van Diepen JA, Tack CJ, Zaki MH, van de Veerdonk FL, Perera D, et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A 2011;108:15324-9.  Back to cited text no. 152
    
153.
Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 2004;20:319-25.  Back to cited text no. 153
    
154.
Sahdo B, Fransrtinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. et al. Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome. PLoS One 2013;8:e75457.  Back to cited text no. 154
    
155.
Roberts RL, Van Rij AM, Phillips LV, Young S, McCormick SP, Merriman TR, et al. Interaction of the inflammasome genes CARD8 and NLRP3 in abdominal aortic aneurysms. Atherosclerosis 2011;218:123-6.  Back to cited text no. 155
    
156.
Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, et al. Lack of interleukin-1β decreases the severity of atherosclerosis in apoE-deficient mice. Arterioscler Thromb Vasc Biol 2003;23:656-60.  Back to cited text no. 156
    
157.
Zhao W, Smith JA, Mao G, Fornage M, Peyser PA, Sun YV, et al. The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region. BMC Med Genomics 2015;8:21.  Back to cited text no. 157
    
158.
Soref CM, Di YP, Hayden L, Zhao YH, Satre MA, Wu R. Characterization of a novel airway epithelial cell-specific short chain alcohol dehydrogenase/reductase gene whose expression is up-regulated by retinoids and is involved in the metabolism of retinol. J Biol Chem 2001;276:24194-202.  Back to cited text no. 158
    
159.
Rhee EJ, Nallamshetty S, Plutzky J. Retinoid metabolism and its effects on the vasculature. Biochim Biophys Acta 2012;1821:230-40.  Back to cited text no. 159
    
160.
Allali-Hassani A, Martinez SE, Peralba JM, Vaglenova J, Vidal F, Richart C, et al. Alcohol dehydrogenase of human and rat blood vessels. Role in ethanol metabolism. FEBS Lett 199717;405:26-30.  Back to cited text no. 160
    
161.
Jelski W, Orywal K, Panek B, Gacko M, Mroczko B, Szmitkowski M. The activity of class I, II, III and IV of alcohol dehydrogenase (ADH) isoenzymes and aldehydedehydrogenase (ALDH) in the wall of abdominal aortic aneurysms. Exp Mol Pathol2009;87:59-62.  Back to cited text no. 161
    
162.
Neuville P, Yan Z, Gidlöf A, Pepper MS, Hansson GK, Gabbiani G, et al. Retinoic acid regulates arterial smooth muscle cell proliferation and phenotypic features in vivo and in vitro through an RARalpha-dependent signaling pathway. Arterioscler Thromb Vasc Biol 1999;19:1430-6.  Back to cited text no. 162
    
163.
Mitra AK, Agrawal DK. In stent restenosis: Bane of the stent era. J Clin Pathol 2006;59:232-9.  Back to cited text no. 163
    
164.
Chadwick CC, Shaw LJ, Winneker RC. TNF-alpha and 9-cis-retinoic acid synergistically induce ICAM-1 expression: Evidence for interaction of retinoid receptors with NF-kappa B. Exp Cell Res 1998;239:423-9.  Back to cited text no. 164
    
165.
Bendich A, Olson JA. Biological actions of carotenoids. FASEB J 1989;3:1927-32.  Back to cited text no. 165
    
166.
Darmanin S, Chen J, Zhao S, Cui H, Shirkoohi R, Kubo N, et al. All-trans retinoic acid enhances murine dendritic cell migration to draining lymph nodes via the balance of matrix metalloproteinases and their inhibitors. J Immunol 2007;179:4616-25.  Back to cited text no. 166
    
167.
Na SY, Kang BY, Chung SW, Han SJ, Ma X, Trinchieri G, et al. Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NFkappaB. J Biol Chem 1999;274:7674-80.  Back to cited text no. 167
    
168.
Gille J, Paxton LL, Lawley TJ, Caughman SW, Swerlick RA. Retinoic acid inhibits the regulated expression of vascular cell adhesion molecule-1 by cultured dermal microvascular endothelial cells. J Clin Invest 1997;99:492-500.  Back to cited text no. 168
    
169.
Saito A, Sugawara A, Uruno A, Kudo M, Kagechika H, Sato Y, et al. All-trans retinoic acid induces in vitro angiogenesis via retinoic acid receptor: Possible involvement of paracrine effects of endogenous vascular endothelial growth factor signaling. Endocrinology 2007;148:1412-23.  Back to cited text no. 169
    
170.
Yoshimura K, Aoki H, Ikeda Y, Furutani A, Hamano K, Matsuzaki M. Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase in mice. Ann N Y Acad Sci 2006;1085:74-81.  Back to cited text no. 170
    
171.
Miyake T, Aoki M, Masaki H, Kawasaki T, Oishi M, Kataoka K, et al. Regression of abdominal aortic aneurysms by simultaneous inhibition of nuclear factor kappaB and ets in a rabbit model. Circ Res 2007;101:1175-84.  Back to cited text no. 171
    
172.
Amaral PP, Dinger ME, Mercer TR, Mattick JS. The eukaryotic genome as an RNA machine. Science 2008;319:1787-9.  Back to cited text no. 172
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]



 

Top
Print this article  Email this article
   
Online since 20th March '04
Published by Wolters Kluwer - Medknow