Progressive Aortic Dilation Is Regulated by miR-17-Associated miRNAs

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.