Selective MicroRNA Suppression in Human Thoracic Aneurysms: Relationship of miR-29a to Aortic Size and Proteolytic Induction (original) (raw)
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Selective MicroRNA Suppression in Human Thoracic Aneurysms
Circulation: Cardiovascular Genetics, 2011
Background— Increasing evidence points to a direct role for altered microRNA (miRNA or miR) expression levels in cardiovascular remodeling and disease progression. Although alterations in miR expression levels have been directly linked to cardiac hypertrophy, fibrosis, and remodeling, their role in regulating gene expression during thoracic aortic aneurysm (TAA) development has yet to be explored. Methods and Results— The present study examined miR expression levels in aortic tissue specimens collected from patients with ascending TAAs by quantitative real-time PCR, and observed decreased miR expression (miRs -1, -21, -29a, -133a, and -486) as compared with normal aortic specimens. A significant relationship between miR expression levels (miRs -1, -21, -29a, and -133a) and aortic diameter was identified; as aortic diameter increased, miR expression decreased. Through the use of a bioinformatics approach, members of the matrix metalloproteinase (MMP) family, proteins involved in TAA ...
Molecular Medicine Reports
Thoracic aortic aneurysm (Taa) and thoracic aortic dissection (Tad) are aortic diseases known as 'silent killers'. While Taa is characterized by an enlargement of at least half of the normal aortic diameter, Tad is characterized by progressive pseudo-lumen formation, which results in the gradual separation of the aortic wall layers. in the present study, a total of 28 serum samples from nine patients with Taa, nine patients with Tad and ten healthy individuals were studied. The aim of the present study was to investigate the expression profiles of hsa-microRNA(miR)-143-3p and hsa-mir-22-3p in Taa and Tad in order to identify candidate mirnas that are responsible for the pathogenesis of the diseases. Following the detection of target mrnas from candidate mirnas by bioinformatic tools, the expression profiles of target mRNAs were analyzed. A quantitative polymerase chain reaction was performed to detect Kirsten rat sarcoma viral oncogene homolog (KraS), mitogen-activated protein kinase (MAPK) 7, MAPK14 and transgelin (TAGLN) mRNA expression profiles. The results of the comparison with control group demonstrated that the increase in the expression levels of hsa-miR-143-3p (P=0.017) and hsa-miR-22 (P=0.03) candidate miRNAs were statistically significant in the TAA group, but not in the Tad group. The expression of KraS and MaPK7 mrnas decreased in the two groups compared with the control group. The level of expression of MAPK14 decreased in the Tad group, but increased in the Taa group compared with the control group. TAGLN mRNA expression level increased in the two groups. The statistically significant difference in the expression of hsa-miR-143-3p suggests that hsa-miR-143-3p may be a potential biomarker for TAA, as the expression of the target mrnas KraS and MaPK7 decreased and the mirna-mrna association was negatively correlated. These mirnas and their associated genes may serve important functions in Taa formation, the altered expression of which may be important in the pathogenesis of Taa.
Journal of Clinical Medicine
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...
A Preliminary microRNA Analysis of Non Syndromic Thoracic Aortic Aneurysms
Balkan journal of medical genetics : BJMG, 2012
The development of thoracic aortic aneurysms (TAAs) involves a multifactorial process resulting in alterations of the structure and composition of the extracellular matrix (ECM). Recently, modifications in microRNA (miRNA) expression were implicated in the pathogenesis of TAA. This study presents a preliminary miRNA microarray analysis conducted on pooled ascending aorta RNAs obtained from non familial non syndromic TAA patients (five males and five females) compared to matched control pools. Ninety-nine differentially expressed miRNAs with >1.5-fold-up- or down-regulation in TAAs compared to controls were identified, 16.0% of which were similarly regulated in the two sexes. Genes putatively targeted by differentially expressed miRNAs belonged preferentially to focal adhesion and adherens junction pathways. The results indicate an altered regulation of miRNA-mediated gene expression in the cellular interactions of aneurysmal aortic wall.
Role of miR-195 in Aortic Aneurysmal Disease
Circulation Research, 2014
The ECM is the key structural component determining dilatation and aneurysm formation in the aortic wall. 8 Abdominal aortic aneurysms (AAAs) are characterized by loss of elastin and increased collagen turnover. Apart from miR-29, the miR-15 family has been implicated in collagen remodeling and the characteristic postnatal silencing of elastin. 9 The miR-15 family consists of 6 highly conserved microRNAs (miR-15a, miR-15b, miR-16-1, miR-16-2, miR-195, and miR-497), which are clustered on 3 separate chromosomes. They have a common seed region (AGCAGCA) and varying degrees of sequence homology in the 3′ region of the mature microRNA. 10 Expression of miR-195 and miR-497 is altered in human aortic specimen
International Journal of Molecular Sciences, 2020
microRNAs (miRNAs) are small RNAs that regulate different biological processes. Our objective was to identify miRNAs dysregulated in plasma and tissue of patients with abdominal aortic aneurysm (AAA) and explore new potential targets involved in AAA. Fifty-seven subjects were recruited for a plasma study (30 AAA patients, 16 healthy volunteers and 11 patients with atherosclerosis). The expression level of 179 miRNAs was screened in plasma from a subset of samples, and dysregulated miRNAs were validated in the entire study population. Dysregulated miRNAs were also quantified in aortic tissue of 21 AAA patients and 8 organ donors. Applying a gene set enrichment analysis, an interaction map of dysregulated miRNAs and their targets was built, and selected targets were quantified in tissue samples. miR-27b-3p and miR-221-3p were overexpressed in plasma of AAA patients compared with healthy controls, 1.6 times and 1.9 times, respectively. In AAA tissue, six miRNAs (miR-1, miR-27b-3p, miR-29b-3p, miR-133a-3p, miR-133b, and miR-195-5p) were underexpressed from 1.6 to 4.8 times and four miRNAs (miR-146a-5p, miR-21-5p, miR-144-3p, and miR-103a-3p) were overexpressed from 1.3 to 7.2 times. Thrombospondin-2, a target of miR-195-5p, was increased in AAA tissue and negatively correlated with the expression of miR-195-5p, suggesting their involvement in a common regulatory mechanism.
MicroRNAs distribution in different phenotypes of Aortic Stenosis
Scientific reports, 2018
Aortic valve stenosis (AVS) represents a cluster of different phenotypes, considering gradient and flow pattern. Circulating micro RNAs may reflect specific pathophysiological processes and could be useful biomarkers to identify disease. We assessed 80 patients (81, 76.7-84 years; 46, 57.5%females) with severe AVS. We performed bio-humoral evaluation (including circulating miRNA-1, 21, 29, 133) and 2D-echocardiography. Patients were classified according to ACC/AHA groups (D1-D3) and flow-gradient classification, considering normal/low flow, (NF/LF) and normal/high gradient, (NG/HG). Patients with reduced ejection fractionwere characterized by higher levels of miRNA1 (p = 0.003) and miRNA 133 (p = 0.03). LF condition was associated with higher levels of miRNA1 (p = 0.02) and miRNA21 (p = 0.02). Levels of miRNA21 were increased in patients with reduced Global longitudinal strain (p = 0.03). LF-HG and LF-LG showed higher levels of miRNA1 expression (p = 0.005). At one-year follow-up mi...
MicroRNA expression signature in human abdominal aortic aneurysms
BMC Medical Genomics, 2012
Background: Abdominal aortic aneurysm (AAA) is a dilatation of the aorta affecting most frequently elderly men. Histologically AAAs are characterized by inflammation, vascular smooth muscle cell apoptosis, and extracellular matrix degradation. The mechanisms of AAA formation, progression, and rupture are currently poorly understood. A previous mRNA expression study revealed a large number of differentially expressed genes between AAA and non-aneurysmal control aortas. MicroRNAs (miRNAs), small non-coding RNAs that are post-transcriptional regulators of gene expression, could provide a mechanism for the differential expression of genes in AAA. Methods: To determine differences in miRNA levels between AAA (n = 5) and control (n = 5) infrarenal aortic tissues, a microarray study was carried out. Results were adjusted using Benjamini-Hochberg correction (adjusted p < 0.05). Real-time quantitative RT-PCR (qRT-PCR) assays with an independent set of 36 AAA and seven control tissues were used for validation. Potential gene targets were retrieved from miRNA target prediction databases Pictar, TargetScan, and MiRTarget2. Networks from the target gene set were generated and examined using the network analysis programs, CytoScape® and Ingenuity Pathway Core Analysis®. Results: A microarray study identified eight miRNAs with significantly different expression levels between AAA and controls (adjusted p < 0.05). Real-time qRT-PCR assays validated the findings for five of the eight miRNAs. A total of 222 predicted miRNA target genes known to be differentially expressed in AAA based on a prior mRNA microarray study were identified. Bioinformatic analyses revealed that several target genes are involved in apoptosis and activation of T cells.
Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development
The Journal of clinical investigation, 2012
MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe-/- mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti-miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expan...