Journal
JOURNAL OF THE AMERICAN HEART ASSOCIATION
Volume 6, Issue 4, Pages -Publisher
WILEY
DOI: 10.1161/JAHA.116.005364
Keywords
aortic valve; calcification; fibroblasts; microRNA; myofibroblast; osteogenesis; phenotypic transition
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Funding
- National Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL106582]
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Background-The transition of aortic valve interstitial cells (AVICs) to myofibroblastic and osteoblast-like phenotypes plays a critical role in calcific aortic valve disease progression. Several microRNAs (miRs) are implicated in stem cell differentiation into osteoblast. We hypothesized that an epigenetic mechanism regulates valvular pro-osteogenic activity. This study examined miR profile in AVICs of calcified valves and identified miRs responsible for AVIC phenotypic transition. Methods and Results-AVICs were isolated from normal and diseased valves. The miR microarray analysis revealed 14 upregulated and 12 downregulated miRs in diseased AVICs. Increased miR-486 and decreased miR-204 levels were associated with higher levels of myofibroblastic biomarker c-smooth muscle actin and osteoblastic biomarkers runt-related transcription factor 2 (Runx2) and osterix (Osx). Cotransfection of miR-486 antagomir and miR-204 mimic in diseased AVICs reduced their ability to express Runx2 and Osx. The miR-486 mimic upregulated c-smooth muscle actin expression in normal AVICs through the protein kinase B pathway and moderately elevated Runx2 and Osx levels. Knockdown of alpha-smooth muscle actin attenuated Runx2 and Osx expression induced by miR-486. The miR-486 mimic and miR-204 antagomir synergistically promoted Runx2 and Osx expression and calcium deposition in normal AVICs and normal aortic valve tissue. Conclusions-In AVICs of calcified valves, increased levels of miR-486 induce myofibroblastic transition to upregulate Runx2 and Osx expression and synergize with miR-204 deficiency to elevate cellular and valvular pro-osteogenic activity. These novel findings indicate that modulation of the epigenetic mechanism underlying valvular pro-osteogenic activity has therapeutic potential for prevention of calcific aortic valve disease progression.
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