MicroRNA/mRNA profiling and regulatory network of intracranial aneurysm

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Abstract

Background

Intracranial aneurysm (IA) is one of the most lethal forms of cerebrovascular diseases characterized by endothelial dysfunction, vascular smooth muscle cell phenotypic modulation, inflammation and consequently loss of vessel cells and extracellular matrix degradation. Besides environmental factors, genetics seem to be a very important factor in the genesis of this disease. Previous mRNA expression studies revealed a large number of differentially expressed genes between IA and control tissue. However, microRNAs (miRNA), small non-coding RNAs which are post-transcriptional regulators of gene expression, have been barely studied. Studying miRNAs could provide a hypothetical mechanism underlying rupture of IA.

Methods

A microarray study was carried out to determine difference in microRNAs and mRNA between patients’ IA tissues and controls. Quantitative RT-PCR assay compared the expression level between two groups (14 IA domes vs. 14 controls) were used for validation. Validated miRNAs were analyzed using Ingenuity Pathway Analysis (IPA) to identify the networks and pathways.

Results

18 miRNAs were confirmed by qPCR to be robustly down-regulated in 14 ruptured IA patients including hsa-mir-133b, hsa-mir-133a, hsa-mir-1, hsa-mir-143-3p, hsa-mir-145-3p, hsa-mir-145-5p, hsa-mir-455-5p, hsa-mir-143-5p, hsa-mir-23b-3p etc., of which 11 miRNAs are clusters: hsa-mir-1/has-mir-133a, hsa-mir-143/hsa-mir-145, hsa-mir-23b/hsa-mir-24-1, and hsa-mir-29b-2/hsa-mir-29c. 12 predicted functions were generated using IPA which showed significant associations with migration of phagocytes, proliferation of mononuclear leukocytes, cell movement of mononuclear leukocytes, cell movement of smooth muscle cells etc.

Conclusion

These data support common disease mechanisms that may be under miRNA control and provide exciting directions for further investigations aimed at elucidating the miRNA mechanisms and targets that may yield new therapies for IA.

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Most cited references 61

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Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis.

Eva van Rooij, Lillian Sutherland, Jeffrey Thatcher … (2008)

Acute myocardial infarction (MI) due to coronary artery occlusion is accompanied by a pathological remodeling response that includes hypertrophic cardiac growth and fibrosis, which impair cardiac contractility. Previously, we showed that cardiac hypertrophy and heart failure are accompanied by characteristic changes in the expression of a collection of specific microRNAs (miRNAs), which act as negative regulators of gene expression. Here, we show that MI in mice and humans also results in the dysregulation of specific miRNAs, which are similar to but distinct from those involved in hypertrophy and heart failure. Among the MI-regulated miRNAs are members of the miR-29 family, which are down-regulated in the region of the heart adjacent to the infarct. The miR-29 family targets a cadre of mRNAs that encode proteins involved in fibrosis, including multiple collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be predicted to derepress the expression of these mRNAs and enhance the fibrotic response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo induces the expression of collagens, whereas over-expression of miR-29 in fibroblasts reduces collagen expression. We conclude that miR-29 acts as a regulator of cardiac fibrosis and represents a potential therapeutic target for tissue fibrosis in general.

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miR-145 and miR-143 Regulate Smooth Muscle Cell Fate Decisions

Kimberly Cordes, Neil T. Sheehy, Mark White … (2009)

SUMMARY microRNAs are regulators of myriad cellular events, but evidence for a single microRNA that can efficiently differentiate multipotent cells into a specific lineage or regulate direct reprogramming of cells into an alternate cell fate has been elusive. Here, we show that miR-145 and miR-143 are co-transcribed in multipotent cardiac progenitors before becoming localized to smooth muscle cells, including neural crest stem cell–derived vascular smooth muscle cells. miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2.5, and were downregulated in injured or atherosclerotic vessels containing proliferating, less differentiated smooth muscle cells. miR-145 was necessary for myocardin-induced reprogramming of adult fibroblasts into smooth muscle cells and sufficient to induce differentiation of multipotent neural crest stem cells into vascular smooth muscle. Furthermore, miR-145 and miR-143 cooperatively targeted a network of transcription factors, including Klf4, myocardin, and Elk-1 to promote differentiation and repress proliferation of smooth muscle cells. These findings demonstrate that miR-145 can direct the smooth muscle fate and that miR-145 and miR-143 function to regulate the quiescent versus proliferative phenotype of smooth muscle cells.

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European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Haemorrhage

Thorsten Steiner, Seppo Juvela, Andreas Unterberg … (2013)

Background: Intracranial aneurysm with and without subarachnoid haemorrhage (SAH) is a relevant health problem: The overall incidence is about 9 per 100,000 with a wide range, in some countries up to 20 per 100,000. Mortality rate with conservative treatment within the first months is 50–60%. About one third of patients left with an untreated aneurysm will die from recurrent bleeding within 6 months after recovering from the first bleeding. The prognosis is further influenced by vasospasm, hydrocephalus, delayed ischaemic deficit and other complications. The aim of these guidelines is to provide comprehensive recommendations on the management of SAH with and without aneurysm as well as on unruptured intracranial aneurysm. Methods: We performed an extensive literature search from 1960 to 2011 using Medline and Embase. Members of the writing group met in person and by teleconferences to discuss recommendations. Search results were graded according to the criteria of the European Federation of Neurological Societies. Members of the Guidelines Committee of the European Stroke Organization reviewed the guidelines. Results: These guidelines provide evidence-based information on epidemiology, risk factors and prognosis of SAH and recommendations on diagnostic and therapeutic methods of both ruptured and unruptured intracranial aneurysms. Several risk factors of aneurysm growth and rupture have been identified. We provide recommendations on diagnostic work up, monitoring and general management (blood pressure, blood glucose, temperature, thromboprophylaxis, antiepileptic treatment, use of steroids). Specific therapeutic interventions consider timing of procedures, clipping and coiling. Complications such as hydrocephalus, vasospasm and delayed ischaemic deficit were covered. We also thought to add recommendations on SAH without aneurysm and on unruptured aneurysms. Conclusion: Ruptured intracranial aneurysm with a high rate of subsequent complications is a serious disease needing prompt treatment in centres having high quality of experience of treatment for these patients. These guidelines provide practical, evidence-based advice for the management of patients with intracranial aneurysm with or without rupture. Applying these measures can improve the prognosis of SAH.

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Author and article information

Contributors

Yugang Jiang

Mingming Zhang

Hua He

Jia Chen

Hua Zeng

Jia Li

Ranhui Duan

Journal

Journal ID (nlm-ta): BMC Med Genomics

Journal ID (iso-abbrev): BMC Med Genomics

Title: BMC Medical Genomics

Publisher: BioMed Central

ISSN (Electronic): 1755-8794

Publication date Collection: 2013

Publication date (Electronic): 30 September 2013

Volume: 6

Page: 36

Affiliations

[1 ]State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan Province, China

[2 ]Department of Neurosurgery, Second Xiang-ya Hospital of Central South University, Changsha, Hunan Province, China

Article

Publisher ID: 1755-8794-6-36

DOI: 10.1186/1755-8794-6-36

PMC ID: 3849943

PubMed ID: 24079748

SO-VID: 86d1669e-991f-4480-8e0d-a8147f13cabe

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

MicroRNA/mRNA profiling and regulatory network of intracranial aneurysm

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Abstract

Background

Methods

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Conclusion

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Most cited references 61

Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis.

miR-145 and miR-143 Regulate Smooth Muscle Cell Fate Decisions

European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Haemorrhage

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