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Abstract 165: Microrna-486 Regulates Fibroblast-to-myofibroblast Transition in Human Aortic Valve Interstitial Cells

Myofibroblasts play an important role in aortic valve fibrosis. In normal aortic valves, the interstitial cells (VICs) are primarily fibroblasts while myofibroblasts are dominant among VICs in stenotic aortic valves. Suppression of VIC phenotypic change may prevent the progression of aortic stenosis. However, the molecular mechanism underlying the fibroblast-to-myofibroblast transition in human VICs is not well understood. We hypothesized that an epigenetic mechanism controls the phenotypic transition in VICs of human aortic valves. Methods and results: Immunoblotting and immunofluorescence staining confirmed that VICs of diseased human aortic valves had higher levels of α-SMA and α-SMA fibers. MicroRNA (miR) microarray and real-time qPCR analysis revealed higher levels of miR-486 in VICs of diseased aortic valves. Lentiviral expression of miR-486 antagomir in diseased VICs markedly suppressed α-SMA expression and α-SMA fiber formation. Conversely, lentiviral expression of miR-486 mimic in normal VICs increased α-SMA levels and enhanced α-SMA fiber formation. Further, expression of miR-486 mimic in normal VICs activated Akt and up-regulated cellular levels of myosin light chain (MLC) kinase. Inhibition of Akt reduced α-SMA expression induced by miR-486 mimic. Inhibition of MLC kinase attenuated α-SMA fiber formation without affecting α-SMA levels. Prolonged treatment of normal VICs with miR-486 increased the production of collagen I, MMP-2 and MMP-9. Stimulation of normal VICs with TGF-β1 or BMP-2 caused a marked increase in cellular miR-486 level that was accompanied by up-regulated α-SMA expression, α-SMA fiber formation and matrix protein production. MiR-486 antagomir suppressed these changes associated with myofibroblastic transition and activity in cells exposed to TGF-β1 or BMP-2. Conclusions: MiR-486 regulates fibroblast-to-myofibroblast transition in human VICs, and pro-fibrogenic factors up-regulate miR-486 expression in VICs. Elevated levels of miR-486 accounts, at least in part, for the myofibroblastic phenotype of VICs in stenotic aortic valves. These novel findings indicate that modulation of miR-486 expression and/or function has therapeutic potential for slowing down the progression of aortic stenosis.