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Published on: August 3, 2018
Altered MicroRNA Expression in Intracranial Aneurysmal Tissues: Possible Role in TGF-β Signaling Pathway
Manjunath Supriya1, Rita Christopher2, Bhagavatula Indira Devi3
1Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, Karnataka, 560029, India.
Abstract:
The molecular mechanisms behind the rupture of intracranial aneurysms remain obscure. MiRNAs are key regulators of a wide array of biological processes altering protein synthesis by binding to target mRNAs. However, variations in miRNA levels in ruptured aneurysmal wall have not been completely examined. We hypothesized that altered miRNA signature in aneurysmal tissues could potentially provide insight into aneurysm pathophysiology. Using a high-throughput miRNA microarray screening approach, we compared the miRNA expression pattern in aneurysm tissues obtained during surgery from patients with aneurysmal subarachnoid hemorrhage (aSAH) with control tissues (GEO accession number GSE161870). We found that the expression of 70 miRNAs was altered. Expressions of the top 10 miRNA were validated, by qRT-PCR and results were correlated with clinical characteristics of aSAH patients. The level of 10 miRNAs (miR-24-3p, miR-26b-5p, miR-27b-3p, miR-125b-5p, miR-143-3p, miR-145-5p, miR-193a-3p, miR-199a-5p, miR-365a-3p/365b-3p, and miR-497-5p) was significantly decreased in patients compared to controls. Expression of miR-125b-5p, miR-143-3p and miR-199a-5p was significantly decreased in patients with poor prognosis and vasospasm. The target genes of few miRNAs were enriched in Transforming growth factor-beta (TGF-β) and Mitogen-activated protein kinases (MAPK) pathways. We found significant negative correlation between the miRNA and mRNA expression (TGF-β1, TGF-β2, SMAD family member 2 (SMAD2), SMAD family member 4 (SMAD4), MAPK1 and MAPK3) in aneurysm tissues. We suggest that miR-26b, miR-199a, miR-497and miR-365, could target multiple genes in TGF-β and MAPK signaling cascades to influence inflammatory processes, extracellular matrix and vascular smooth muscle cell degradation and apoptosis, and ultimately cause vessel wall degradation and rupture.
Insights
Altered microRNA (miRNA) levels in ruptured brain aneurysm tissues offer new insights into aneurysm pathophysiology. Specific miRNAs may regulate pathways involved in vessel wall degradation and rupture.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- The molecular mechanisms driving intracranial aneurysm rupture are not fully understood.
- MicroRNAs (miRNAs) are crucial regulators of cellular processes, influencing protein synthesis by interacting with messenger RNAs (mRNAs).
- Previous research has not comprehensively analyzed miRNA expression variations in ruptured aneurysm walls.
Purpose of the Study:
- To investigate the miRNA expression profile in tissues from patients with aneurysmal subarachnoid hemorrhage (aSAH).
- To identify specific miRNAs associated with aneurysm pathophysiology and patient prognosis.
- To explore the potential roles of altered miRNAs in transforming growth factor-beta (TGF-β) and mitogen-activated protein kinase (MAPK) signaling pathways.
Main Methods:
- High-throughput miRNA microarray screening was employed to compare miRNA expression in aneurysm tissues versus control tissues.
- Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the expression levels of top miRNAs.
- Correlation analysis was performed between miRNA expression, mRNA expression, and clinical characteristics of aSAH patients.
Main Results:
- A significant alteration in the expression of 70 miRNAs was observed in aneurysm tissues.
- Ten specific miRNAs (miR-24-3p, miR-26b-5p, miR-27b-3p, miR-125b-5p, miR-143-3p, miR-145-5p, miR-193a-3p, miR-199a-5p, miR-365a-3p/365b-3p, and miR-497-5p) showed significantly decreased levels in patients compared to controls.
- Decreased expression of miR-125b-5p, miR-143-3p, and miR-199a-5p correlated with poor prognosis and vasospasm.
- Negative correlations were found between specific miRNA and mRNA expressions within the TGF-β and MAPK pathways.
- Target genes of several miRNAs were enriched in TGF-β and MAPK signaling pathways.
Conclusions:
- The study identified a distinct miRNA signature in ruptured intracranial aneurysms.
- Specific miRNAs, including miR-26b, miR-199a, miR-497, and miR-365, may play a role in regulating TGF-β and MAPK signaling.
- These miRNAs could influence inflammatory processes, extracellular matrix degradation, vascular smooth muscle cell apoptosis, and ultimately contribute to vessel wall weakening and rupture.
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