Title Tissue-specific miRNAs regulate the development of thoracic aortic aneurysm: the emerging role of KLF4 network /
Authors Gasiulė, Stasė ; Stankevičius, Vaidotas ; Patamsytė, Vaiva ; Ražanskas, Raimundas ; Žukovas, Giedrius ; Kapustina, Žana ; Žaliaduonytė, Diana ; Benetis, Rimantas ; Lesauskaitė, Vaiva ; Vilkaitis, Giedrius
DOI 10.3390/jcm8101609
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Is Part of Journal of Clinical Medicine.. Basel : MDPI. 2019, vol. 8, no. 10, 1609, p. 1-16.. ISSN 2077-0383
Keywords [eng] Aortic aneurysm, thoracic ; MicroRNAs ; TGF-β pathway ; Kruppel-like transcription factors ; Transforming growth factor beta ; Signal transduction ; Gene expression
Abstract [eng] 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.
Published Basel : MDPI
Type Journal article
Language English
Publication date 2019