Defining the Role of the miR-145—KLF4—αSMA Axis in Mitral Valvular Interstitial Cell Activation in Myxomatous Mitral Valve Prolapse Using the Canine Model

Defining the Role of the miR-145—KLF4—αSMA Axis in Mitral Valvular Interstitial Cell Activation in Myxomatous Mitral Valve Prolapse Using the Canine Model

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 occur...

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Bibliographic Details
Main Authors: Vicky K. Yang, Nicole Moyer, Runzi Zhou, Sally Z. Carnevale, Dawn M. Meola, Sally R. Robinson, Guoping Li, Saumya Das
Format: Article
Language:English
Published: MDPI AG 2024-01-01
Series:International Journal of Molecular Sciences
Subjects:
mitral valve prolapse
animal model
non-coding RNA
extracellular vesicles
translational model
Online Access:https://www.mdpi.com/1422-0067/25/3/1468
Description
Summary: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. <i>miR-145</i> was shown to be upregulated in both the affected VICs and sEV, and overexpression of <i>miR-145</i> by mimic transfection in quiescent VIC recapitulates the activated myofibroblastic phenotype. Concurrently, KLF4 expression was noted to be suppressed by <i>miR-145</i>, confirming the <i>miR-145</i>—KLF4—αSMA axis. Targeting this axis may serve as a potential therapy in controlling pathologic abnormalities found in MVP valves.
ISSN:1661-6596
1422-0067

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