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Published on: February 23, 2020
Progressive Aortic Dilation Is Regulated by miR-17-Associated miRNAs
Jie Wu1, Hui-Fang Song2, Shu-Hong Li3
1Laboratory of Medical Genetics, Harbin Medical University, Harbin, China; Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
Background:
Patients with a bicuspid aortic valve (BAV) are at increased risk for progressive aortic dilation associated with extracellular matrix (ECM) degradation by matrix metalloproteinases (MMP). However, the mechanisms responsible for initiating this process are unknown. In the heart, MMP activity is regulated by micro-ribonucleic acid-17 (miR-17)-related downregulation of tissue inhibitors of metalloproteinases (TIMP); a similar process may exist in the aorta.
Objectives:
This study sought to ascertain whether aortic matrix degradation in BAV patients progresses by miR-17-related miRNA regulation of TIMP-MMP.
Methods:
To eliminate confounding patient-related factors, severely dilated and less dilated aortic tissue samples were collected from 12 BAV patients. Gene and protein expression levels were evaluated in paired tissue samples from the same patient and were compared to aortic samples from 16 patients with aortas that appeared to be normal.
Results:
Gene expression analyses confirmed increased expression of miR-17-related miRNAs in less dilated compared with severely dilated tissue from the same patient or normal aortic sample. TIMP-1, -2, and -3 were significantly decreased, and MMP2 activity was significantly increased in less dilated samples, suggesting that this normal-looking tissue was in the early stages of ECM degradation. Smooth muscle cells isolated from normal or BAV aortas transfected with an miR-17 mimic had decreased TIMP-1 and -2 expression and increased MMP2 activity, whereas the opposite effects were seen with an miR-17 inhibitor, suggesting that miR-17 may control the TIMP-MMP balance in these tissues. Luciferase reporter assays demonstrated that miR-17 regulated TIMP-1 and -2 expression.
Conclusions:
Our in vitro and in vivo studies taken together confirm that miR-17 directly regulates TIMP-1 and -2. Less dilated aortic BAV tissue may be in the initial stages of dilation under the control of miR-17-related miRNAs. New therapies that inhibit these miRNAs may prevent aortic dilation.
Insights
MicroRNA-17 (miR-17) regulates tissue inhibitors of metalloproteinases (TIMPs) and matrix metalloproteinases (MMPs) in bicuspid aortic valve (BAV) patients, potentially initiating aortic dilation. Inhibiting miR-17 may prevent this progression.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Genetics
Background:
- Bicuspid aortic valve (BAV) patients face increased risk of aortic dilation due to extracellular matrix (ECM) degradation by matrix metalloproteinases (MMPs).
- The initiating mechanisms of ECM degradation in BAV-associated aortic dilation remain unclear.
- MicroRNA-17 (miR-17) regulates MMP activity in the heart by downregulating tissue inhibitors of metalloproteinases (TIMPs), suggesting a similar mechanism in the aorta.
Purpose of the Study:
- To investigate if miR-17-related microRNA (miRNA) regulation of TIMP-MMP pathways drives aortic matrix degradation in BAV patients.
- To elucidate the role of miR-17 in the early stages of aortic dilation in BAV.
Main Methods:
- Comparative analysis of gene and protein expression in paired aortic tissues from BAV patients with varying dilation severity and normal controls.
- In vitro studies using smooth muscle cells to assess the impact of miR-17 mimics and inhibitors on TIMP and MMP expression and activity.
- Luciferase reporter assays to confirm direct regulation of TIMP-1 and TIMP-2 by miR-17.
Main Results:
- Increased miR-17 expression was observed in less dilated BAV aortic tissue compared to severely dilated or normal tissue.
- TIMP-1, -2, and -3 levels were decreased, while MMP2 activity was increased in less dilated BAV tissues, indicating early ECM degradation.
- In vitro experiments demonstrated that miR-17 directly regulates TIMP-1 and TIMP-2 expression, influencing MMP2 activity.
Conclusions:
- miR-17 directly controls TIMP-1 and TIMP-2 expression, impacting the TIMP-MMP balance in aortic tissue.
- Less dilated BAV aortic tissue exhibits early-stage dilation driven by miR-17-related miRNAs.
- Targeting miR-17 with inhibitory therapies presents a potential strategy to prevent aortic dilation in BAV patients.
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