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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

Yang, Vicky1

Published Jan 16, 2024 on Dryad. https://doi.org/10.5061/dryad.dz08kps4h

Data files

Jan 16, 2024 version files 1.84 MB

Abstract

Mitral valve prolapse (MVP) is a common valvular disease, affecting 2-3% of the adult human population and is a degenerative condition. 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 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 suppressed by miR-145, and KLF4 overexpression resulted in a decrease in αSMA expression, and its suppression resulted in an increase in αSMA expression, thus confirming the miR-145 – KLF4 – αSMA axis. Targeting this axis may serve as potential therapy in controlling pathologic abnormalities found in MVP valves.