MicroRNA-204 Deficiency in Human Aortic Valves Elevates Valvular Osteogenic Activity.

Rui Song,Yufeng Zhai,Xianzhong Meng,Lihua Ao,David A. Fullerton

doi:10.3390/ijms21010076

Rui Song, Yufeng Zhai + Show 3 more

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https://doi.org/10.3390/ijms21010076

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Abstract

Aortic valve interstitial cells (AVICs) play a major role in valvular calcification associated with calcific aortic valve disease (CAVD). Although AVICs from diseased valves display a pro-osteogenic phenotype, the underlying mechanism causing this remains unclear. MicroRNA-204 (miR-204) is a negative regulator of osteoblast differentiation. We sought to analyze miR-204 expression in diseased human aortic valves and determine the role of this miR in AVIC osteogenic activity associated with CAVD pathobiology. In situ hybridization and PCR analysis revealed miR-204 deficiency in diseased valves and in AVICs from diseased valves. MiR-204 mimic suppressed alkaline phosphatase (ALP) expression and calcium deposition in AVICs from diseased valves. MiR-204 antagomir enhanced ALP expression in AVICs from normal valves through induction of Runx2 and Osx, and expression of miR-204 antagomir in mouse aortic valves promoted calcium deposition through up-regulation of Runx2 and Osx. Further, miR-204 mimic suppressed the osteogenic responses to TGF-β1 in AVICs of normal valves. In conclusion, miR-204 deficiency contributes to the mechanism underlying elevated osteogenic activity in diseased aortic valves, and miR-204 is capable of reversing the pro-osteogenic phenotype of AVICs of diseased valves and suppressing AVIC osteogenic response to stimulation. Exogenous miR-204 may have therapeutic potential for inhibiting valvular calcification associated with CAVD progression.

Highlights

Calcific aortic valve disease (CAVD) is one of the most prevalent cardiovascular diseases in elderly people (65 or older)
The results of in vitro experiments demonstrate that miR-204 mimic suppresses the osteogenic activity in Aortic valve interstitial cells (AVICs) of diseased valves whereas miR-204 antagomir enhances the osteogenic activity in AVICs of normal valves
These findings suggest that miR-204 is a negative regulator of valvular osteogenic activity and that miR-204 deficiency contributes to the mechanism of valvular calcification in CAVD

Summary

Introduction

Calcific aortic valve disease (CAVD) is one of the most prevalent cardiovascular diseases in elderly people (65 or older). In many patients this disease progresses to symptomatic severe aortic stenosis, a clinical entity for which costly aortic valve replacement is needed. The pathobiology of CAVD involves nodular calcification of valvular leaflets, and progressive valvular calcification is a major cause of morbidity and mortality in patients with CAVD [1,2]. Clinically significant aortic stenosis takes years to develop. The slow progressive course of CAVD affords a wide window for pharmacological intervention to halt disease progression. Gaps in our knowledge of the mechanisms underlying CAVD progression impede the development of pharmacological therapies [3,4]

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