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Open AccessArticle

Tissue-Specific miRNAs Regulate the Development of Thoracic Aortic Aneurysm: The Emerging Role of KLF4 Network

1
Institute of Biotechnology, Vilnius University, LT-10257 Vilnius, Lithuania
2
Institute of Cardiology, Lithuanian University of Health Sciences, LT-50103 Kaunas, Lithuania
3
Department of Cardiac, Thoracic and Vascular Surgery, Lithuanian University of Health Sciences, LT-50103 Kaunas, Lithuania
4
Thermo Fisher Scientific Baltics, LT-02241 Vilnius, Lithuania
5
Department of Cardiology, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this manuscript.
J. Clin. Med. 2019, 8(10), 1609; https://doi.org/10.3390/jcm8101609
Received: 5 August 2019 / Revised: 27 September 2019 / Accepted: 27 September 2019 / Published: 3 October 2019
(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)
MicroRNAs (miRNAs) are critical regulators of the functional pathways involved in the pathogenesis of cardiovascular diseases. Understanding of the disease-associated alterations in tissue and plasma will elucidate the roles of miRNA in modulation of gene expression throughout development of sporadic non-syndromic ascending thoracic aortic aneurysm (TAA). This will allow one to propose relevant biomarkers for diagnosis or new therapeutic targets for the treatment. The high-throughput sequencing revealed 20 and 17 TAA-specific miRNAs in tissue and plasma samples, respectively. qRT-PCR analysis in extended cohort revealed sex-related differences in miR-10a-5p, miR-126-3p, miR-155-5p and miR-148a-3p expression, which were the most significantly dysregulated in TAA tissues of male patients. Unexpectedly, the set of aneurysm-related miRNAs in TAA plasma did not resemble the tissue signature suggesting more complex organism response to the disease. Three of TAA-specific plasma miRNAs were found to be restored to normal level after aortic surgery, further signifying their relationship to the pathology. The panel of two plasma miRNAs, miR-122-3p, and miR-483-3p, could serve as a potential biomarker set (AUC = 0.84) for the ascending TAA. The miRNA-target enrichment analysis exposed TGF-β signaling pathway as sturdily affected by abnormally expressed miRNAs in the TAA tissue. Nearly half of TAA-specific miRNAs potentially regulate a key component in TGF-β signaling: TGF-β receptors, SMADs and KLF4. Indeed, using immunohistochemistry analysis we detected increased KLF4 expression in 27% of TAA cells compared to 10% of non-TAA cells. In addition, qRT-PCR demonstrated a significant upregulation of ALK1 mRNA expression in TAA tissues. Overall, these observations indicate that the alterations in miRNA expression are sex-dependent and play an essential role in TAA via TGF-β signaling. View Full-Text
Keywords: aortic disease; aneurysm; miRNA; TGF-β pathway; KLF4; synthetic phenotype aortic disease; aneurysm; miRNA; TGF-β pathway; KLF4; synthetic phenotype
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Gasiulė, S.; Stankevičius, V.; Patamsytė, V.; Ražanskas, R.; Žukovas, G.; Kapustina, Ž.; Žaliaduonytė, D.; Benetis, R.; Lesauskaitė, V.; Vilkaitis, G. Tissue-Specific miRNAs Regulate the Development of Thoracic Aortic Aneurysm: The Emerging Role of KLF4 Network. J. Clin. Med. 2019, 8, 1609.

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