Keywords

MicroRNA; Intracranial aneurysm; Biomarkers

Introduction

Intracranial aneurysms (IAs), also referred to as cerebral aneurysms, are sac-like dilatations of arteries inside the brain [1]. About a 2-3% of the general population is affected by IAs [2]. Most of the patients with an unruptured IAs are asymptomatic, however, IAs rupture can cause a sever type of stroke known as Subarachnoid hemorrhage (SAH) [3]. The SAH is a devastating condition that affects mostly young people (mean age 50 years), of whom a third dies and 50% of survivors are left disabled [4]. This neurological injuries seriously affect the quality of life not only in the economic point of view [5] but also for their secondary complications like rebleeding, early brain injury, cerebral vasospasm, delayed cerebral ischemia and chronic hydrocephalus [6]. As well as extracerebral organ dysfunctions [7].

Despite the efforts of many research groups in understanding the IAs physiopathology [8] and the brain mechanisms that triggers the aneurysm rupture combined with the advances of new surgical and endovascular techniques, the SAH derived from ruptured IAs still remains a challenge for neurosurgeons.

Some of the recent studies identified pro-inflammatory molecules as potential biomarkers [9] based on the role of extracellular matrix turnover factors and inflammatory factors, such as interleukin (IL)-1β, IL-6, IL-8, IL-18, interferon-γ, tumor necrosis factor-α and major histocompatibility complex class II gene, in the development, progression, and rupture of aneurysms [10]. However, new evidence is pointing MicroRNAs (miRNAs/MiR`s) as major switches to mediated post-transcriptional regulation for the proper functioning of cardiovascular homeostasis [11] and fundamental keys in IAs development pathways [12]. This work briefly review the potential role of MiR`s as new biomarkers and therapeutic targets.

Micrornas in Ias Pathogenesis

MiRNAs are single-stranded small noncoding RNAs that consist of approximately 22 nucleotides [13]. This molecules have been involved in a wide range of biological process including vascular diseases. In IAs pathogenesis vascular smooth muscle cells (VSMCs) plays a critical role [14]. VSMCs possess the ability to modulate their phenotype in response to changing local environmental cues [15]. The phenotypic changes in VSMCs improves the migration, proliferation, and production of extracellular matrix components [16]. In this phenotypic expression the MiR`s have seen to modulate functional pathways, the MiR-145 is the most abundant miRNA in vascular walls [17] and recently it`s been proposed for a novel VSMCs phenotypic marker. Preclinical models showed that MiR-145 mediate phenotypic effects through KLF5/myocardin pathway while in clinical studies it was found that rs4705342 TC and TC/CC genotypes in the promoter of the miR-143/145 cluster are related to a lower risk of IA [18]. However, there is still unknown the details of this mechanisms.

The MiR-34a has been reported to regulate vascular smooth muscle cell (VSMC) differentiation from stem cells in vitro and in vivo [19] by reducing Notch1 expression levels, regulator in VSMC functions and arterial remodeling. MiR`s expression are also altered after vascular injury, miR-133 plays a modulatory role in VSMC phenotypic switching [20] and others like the miR-21 and miR-221/222 have a modest effect on neointimal growth. Recently, miR-125 was also involve in modulating the cell proliferation of vascular smooth muscle cells taking as a target the nitric oxide synthase 1 (NOS1) gene [21]. Most of the MiR`s are yet to reveal they role in IAs formation through VSMC proliferation and phenotypical expression. However, the MiR`s could represent a novel tool as biomarkers to predict the patients progression and the best therapeutic targets. In Figure 1 is represented the MiR`s intervention IAs biogenesis.

Figure 1: Schematic representation of MiR`s contribution in IAs formation and progression through modulation of Transcriptional Factors, development of inflammatory response and phenotypic changes in VSMC. The crucial role of MiR`s in IAs pathogenesis and rupture make them ideals candidates as biomarkers and future therapeutic targets. VSMC (vascular smooth muscle cell), ECM (Extracellular Matrix).

MiR`s Expression in IAs patients

As was previously mentioned, the MiR-145 has been propose for a novel biomarker, for its central role in vascular proliferative diseases. In peripheral blood of SAH patients, a microarray study indicated that 86 miRNAs were significantly dysregulated [22]. Recently, it was reported that patients with low miR-29a expression had longer disease-free survival (DFS) and overall survival (OS) than those with high miR-29a expression [23]. In other case-control study, lower levels of let-7a in plasma were associated with highest risk for the development of IA [24]. The MiR`s 132 and 324 were also found to upregulate in aneurysmal subarachnoid hemorrhage suggesting a role of this MiR`s in the rupture of IAs [25]. In relation with cytokines, in patients with abdominal aortic aneurysm (AAA), MCP-1 is negative correlated with miRs 146a,-124,-223, the TNFα with miRs-123 and -226 and the TFGβ with miR-146a, suggesting that miRs expression changes are correlated closely with inflammatory process in vascular diseases [26].

Some studies have associated the odds ratio values of MiR`s in IAs patients. The miR‐16 and miR‐25 levels in plasma were significantly changed in patients with either ruptured or unruptured IAs [27]. The MiR`s -21, miRNA-22 miRNA-720 and miRNA-3665 also increase their expression in IA patients compared to healthy patients [28]. Finally most recent studies identified MiR-29b downregulation induced VSMCs phenotypic modulation by directly activating ATG14-mediated autophagy, which is associated with the formation, growth and rupture of IAs [29].

Final Remarks and Conclusions

Based on the recent studies about the MiR`s modulations in the IAs pathological pathways through target specific genes involved in development, progression, and rupture of aneurysms. MiR`s appear to be a potential tool as molecular biomarkers with high specificity and sensibility. As in other fields, like cancer research, nanomedicine has shown immense potential in advancing treatment regimens [30] so for neurosurgery practice, the use of antogomirs or miRs in nanoparticles could enhance patient’s outcome. However, there´s still some challenges, like the chemotherapeutic agents needs a particular target in oncology therapeutics, the drug delivery is fraught with many limitations [31], in the case of IAs, the nanocarriers system needs to target especific receptors or proteins or such other regions of interest otherwise the stealth capacity of these carriers is compromised and eventually they will be rapidly cleared by the liver, spleen and other RES organs thus showing very little accumulation in aneurysm regions [32]. Summing up, miRNAs could change the prognosis, outcome and quality of life of patients but their connection with target genes requires much efforts before their expression analysis is applied in the clinical diagnosis and treatment of intracranial aneurysm [22].

Conflict of Interest

None to declare.

References

1. Wang K, Wang X, Lv H, Cui C, Leng J, et al. Identification of the miRNA-target gene regulatory network in intracranial aneurysm based on microarray expression data. Exp Ther Med 13: 3239-3248.
2. Brown RD (2010) Unruptured intracranial aneurysms. Semin Neurol 30: 537-544.
3. Meeuwsen JAL, van ´t Hof FNG, van Rheenen W, Rinkel GJE, Veldink JH, et al. (2017) Circulating microRNAs in patients with intracranial aneurysms. PLoS ONE 12: e0176558.
4. Nieuwkamp DJ, Setz LE, Algra A, Linn FH (2009) Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex and region: A meta-analysis. Lancet Neurol 8: 635-642.
5. Connollyyg ES, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, et al. (2012) Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association, Stroke. A J Cerebral Circulation. 43: 1711-1737.
6. Shimamura N, Ohkuma H (2014) Phenotypic transformation of smooth muscle in vasospasm after aneurysmal subarachnoid hemorrhage. Transl Stroke Res 5: 357-364.
7. Chen S, Li Q, Wu H, Krafft PR, Wang Z, et al. (2014) The Harmful Effects of Subarachnoid Hemorrhage on Extracerebral Organs. Biomed Res Int 2014: 858496.
8. Pera J, Korostynski M, Krzyszkowski T, Czopek J, Slowik A, et al. (2010) Gene expression profiles in human ruptured and unruptured intracranial aneurysms: what is the role of inflammation. Stroke 41: 224-231.
9. Kao HW, Lee KW, Kuo CL, Huang CS, Tseng WM, et al. (2015) Interleukin-6 as a prognostic biomarker in ruptured intracranial aneurysms. PLoS One 10: e0132115.
10. Sathyan S, Koshy LV, Srinivas L, Easwer HV, Premkumar S, Nair S, et al. Pathogenesis of intracranial aneurysm is mediated by proinflammatory cytokine TNFA and IFNG and through stochastic regulation of IL10 and TGFB1 by comorbid factors. J Neuroinflammation 12: 135.
11. Condorelli G, Latronico MV, Cavarretta E (2014) microRNAs in cardiovascular diseases: current knowledge and the road ahead. J Am Coll Cardiol 63: 2177-2187.
12. Small EM, Frost RJ, Olson EN (2010) MicroRNAs add a new dimension to cardiovascular disease. Circulation 121: 1022-1032.
13. Unda, Santiago R, Villegas, Emilce A (2017) MicroRNA: A Major Key in Pain Neurobiology. Int J cell Sci & mol boil 3: 1-7.
14. Starke RM, Chalouhi N, Ding D, Raper DM, Mckisic MS, et al. (2014) Vascular smooth muscle cells in cerebral aneurysm pathogenesis. Transl Stroke Res 5: 338-346.
15. Owens GK, Kumar MS, Wamhoff BR (2004) Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84: 67-801.
16. Cheng Y, Liu X, Yang J, Lin Y, Xu DZ, et al. (2009) MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ Res 105: 158-166.
17. Ji R, Cheng Y, Yue J, Yang J, Liu X, et al. (2007) MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ Res 100: 1579-1588.
18. Sima X, Sun H, Zhou P, You C, Cai B (2017) Association between functional polymorphisms in the promoter of the miR-143/145 cluster and risk of intracranial aneurysm. Sci Rep 7: 43633.
19. Xiao Q, Chen Q, Feng Y (2015) miRNA-34a reduces neointima formation through inhibiting smooth muscle cell proliferation and migration. J Mol Cell Cardiol 101: A116-A116.
20. Torella D, Iaconetti C, Catalucci D, Ellison GM, Leone A, et al. (2011) MicroRNA-133 controls vascular smooth muscle cell phenotypic switch in vitro and vascular remodeling in vivo. Circ Res 109: 880-893.
21. Wei L, Wang Q, Zhang Y, Yang C, Guan H, et al. Identification of key genes, transcription factors and microRNAs involved in intracranial aneurysm. Mol Med Rep 17: 891-897.
22. Huang F, Yi J, Zhou T, Gong X, Jiang H, et al. (2017) Toward Understanding Non-coding RNA Roles in Intracranial Aneurysms and Subarachnoid Hemorrhage. Transl Neurosci 8: 54-64.
23. Wang WH, Wang YH, Zheng LL, Li XW, Hao F, et al. (2016) MicroRNA-29a: A potential biomarker in the development of intracranial aneurysm. J Neurol Sci 364: 84-89.
24. Sima X, Sun H, Zhou P, You C (2015) A Potential Polymorphism in the Promoter of Let-7 is Associated With an Increased Risk of Intracranial Aneurysm: A Case-Control Study. Medicine 94: e2267.
25. Su XW, Chan AHY, Lu G, Lin M, Sze J, et al. (2015) Circulating microRNA 132-3p and 324-3p Profiles in Patients after Acute Aneurysmal Subarachnoid Hemorrhage. PLoS ONE 10: e0144724.
26. Kin K, Miyagawa S, Fukushima S (2012) Tissue- and Plasma-Specific MicroRNA Signatures for Atherosclerotic Abdominal Aortic Aneurysm. J Am Heart Assoc 1: e000745.
27. Li P, Zhang Q, Wu X, Yang X, Zhang Y (2014) Circulating microRNAs Serve as Novel Biological Markers for Intracranial Aneurysms. J Am Heart Assoc 3: e000972.
28. Jin H, Li C, Ge H, Jiang Y, Li Y (2013) Circulating microRNA: a novel potential biomarker for early diagnosis of Intracranial Aneurysm Rupture a case control study. J Transl Med 11: 296.
29. Sun L, Zhao M, Zhang J, Lv M, Li Y, et al. (2017) MiR-29b Downregulation Induces Phenotypic Modulation of Vascular Smooth Muscle Cells: Implication for Intracranial Aneurysm Formation and Progression to Rupture. Cell Physiol Biochem 41: 510-518.
30. Wakaskar RR (2017) Promising effects of nanomedicine in cancer drug delivery. J Drug Target 18: 1-6.
31. Wakaskar RR (2017) Challenges Pertaining to Adverse Effects of Drugs. Int J Drug Dev & Res 9: 1-2.
32. Wakaskar RR (2017) Passive and Active Targeting in Tumor Microenvironment. IJDDR 9: 37-41.