Abstract
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.
Highlights
Thoracic aortic aneurysms (TAAs) are usually silent and deadly if not detected and repaired on time [1]
In order to determine miRNAs which expression levels are potentially deregulated in aorta tissue and blood plasma during the formation of TAA, in the present study we evaluated miRNA expression profiles in a learning set of patient tissue and plasma samples (n = 32) using Illumina high-throughput miRNA sequencing platform (Table 1; Figure 1A)
The overview of miRNA-Seq experimental design and data quality is depicted in Supplementary Results. miRNA-Seq data analysis revealed a total of 20 differentially expressed miRNAs in TAA tissue samples compared to non-TAA group (Table 2), among which the majority (15 of 20 miRNAs) were upregulated (Table 3)
Summary
Thoracic aortic aneurysms (TAAs) are usually silent and deadly if not detected and repaired on time [1]. For the last few decades, VSMC dedifferentiation has been recognized as one of the key processes involved in arterial maintenance and development of vascular diseases [9]. This led to the identification of various regulators of VSMC phenotype including a transcription activator myocardin (MyoCD) [10], transcription factor Krüppel-like factor 4 (KLF4) [11], and components of a transforming growth factor beta (TGF-β) signalling pathway [12]. During the formation of TAA, VSMCs are thought to lose their contractile ability and start secretion of various extracellular matrix proteins and their inhibitors, but the mechanism of this phenotypic shift remains unknown
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call