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Murine Surgical Model of Topical Elastase Induced Descending Thoracic Aortic Aneurysm
Published on: August 24, 2019
Selective microRNA suppression in human thoracic aneurysms: relationship of miR-29a to aortic size and proteolytic
Jeffrey A Jones1, Robert E Stroud, Elizabeth C O'Quinn
1Cardiothoracic Surgery Research, Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
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 development, were examined for putative miR binding sites. MMP-2 and MMP-9 were identified as potential targets for miR-29a and miR-133a, respectively, and MMP-2 was subsequently verified as a miR-29a target in vitro. A significant inverse relationship between miR-29a and total MMP-2 was then identified in the clinical TAA specimens.
Conclusions:
These findings demonstrate altered miR expression patterns in clinical TAA specimens, suggesting that the loss of specific miR expression may allow for the elaboration of specific MMPs capable of driving aortic remodeling during TAA development. Importantly, these data suggest that these miRs have biological and clinical relevance to the behavior of TAAs and may provide significant targets for therapeutic and diagnostic applications.
Insights
Decreased microRNA (miRNA) expression in thoracic aortic aneurysm (TAA) tissues correlates with larger aortic diameters and increased matrix metalloproteinases (MMPs), suggesting miRNAs as potential therapeutic targets for TAA.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
Background:
- Altered microRNA (miRNA) expression is implicated in cardiovascular remodeling.
- The role of miRNAs in thoracic aortic aneurysm (TAA) development remains unexplored.
Purpose of the Study:
- To investigate miRNA expression patterns in TAA patient tissues.
- To identify potential miRNA targets involved in TAA pathogenesis.
Main Methods:
- Quantitative real-time PCR was used to measure miRNA levels in TAA specimens.
- Bioinformatics analysis identified potential miRNA-matrix metalloproteinase (MMP) interactions.
- In vitro experiments validated MMP-2 as a miR-29a target.
Main Results:
- Specific miRNAs (miR-1, -21, -29a, -133a, -486) were downregulated in TAA tissues.
- Decreased miRNA expression correlated with increased aortic diameter.
- miR-29a and miR-133a were predicted to target MMP-2 and MMP-9, respectively; MMP-2 was confirmed as a miR-29a target.
Conclusions:
- Downregulation of specific miRNAs in TAA is associated with increased MMP activity.
- These miRNAs may play a critical role in TAA development and progression.
- Targeting these miRNAs could offer novel therapeutic and diagnostic strategies for TAA.
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