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Defining the Role of the miR-145-KLF4-αSMA Axis in Mitral Valvular Interstitial Cell Activation in Myxomatous Mitral
Vicky K Yang1, Nicole Moyer1, Runzi Zhou1
1Department of Clinical Science, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA.
Abstract:
Mitral valve prolapse (MVP) is a common valvular disease, affecting 2-3% of the adult human population and is a degenerative condition. A total of 5-10% of the afflicted will develop severe mitral regurgitation, cardiac dysfunction, congestive heart failure, and sudden cardiac death. Naturally occurring myxomatous MVP in dogs closely resembles MVP in humans structurally, and functional consequences are similar. In both species, valvular interstitial cells (VICs) in affected valves exhibit phenotype consistent with activated myofibroblasts with increased alpha-smooth muscle actin (αSMA) expression. Using VICs collected from normal and MVP-affected valves of dogs, we analyzed the miRNA expression profile of the cells and their associated small extracellular vesicles (sEV) using RNA sequencing to understand the role of non-coding RNAs and sEV in MVP pathogenesis. miR-145 was shown to be upregulated in both the affected VICs and sEV, and overexpression of miR-145 by mimic transfection in quiescent VIC recapitulates the activated myofibroblastic phenotype. Concurrently, KLF4 expression was noted to be suppressed by miR-145, confirming the miR-145-KLF4-αSMA axis. Targeting this axis may serve as a potential therapy in controlling pathologic abnormalities found in MVP valves.
Insights
Mitral valve prolapse (MVP) involves activated myofibroblasts. Upregulated miR-145 in valvular interstitial cells and extracellular vesicles drives this activation, suggesting a therapeutic target for MVP.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Extracellular Vesicle Research
Background:
- Mitral valve prolapse (MVP) is a common degenerative valvular disease with serious complications.
- Canine MVP models offer structural and functional similarities to human disease.
- Activated valvular interstitial cells (VICs) with increased alpha-smooth muscle actin (αSMA) characterize MVP.
Purpose of the Study:
- To investigate the role of non-coding RNAs and small extracellular vesicles (sEV) in MVP pathogenesis.
- To analyze miRNA expression profiles in VICs and sEV from normal and MVP-affected canine valves.
Main Methods:
- RNA sequencing of VICs and associated sEV from normal and MVP canine valves.
- miRNA expression profiling to identify key regulatory molecules.
- In vitro transfection of VICs with miR-145 mimics to assess functional impact.
Main Results:
- miR-145 was significantly upregulated in both MVP-affected VICs and sEV.
- Overexpression of miR-145 in quiescent VICs induced an activated myofibroblastic phenotype.
- miR-145 was confirmed to suppress KLF4 expression, establishing the miR-145-KLF4-αSMA axis.
Conclusions:
- The miR-145-KLF4-αSMA axis plays a critical role in MVP pathogenesis.
- Targeting this axis presents a potential therapeutic strategy for mitigating MVP-associated valvular abnormalities.
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