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The Role of Stretch Responsive microRNAs in Aortic Valve Disease : : miR-148a Repression of NF-kappaB Mediated Inflammation and miR-19b Modulation of Osteogenic Pathways


Aortic valve stenosis is the third most common form of heart disease and afflicted individuals are at risk for infective endocarditis, congestive heart failure, or death. Having a bicuspid aortic valve is the highest risk factor for developing calcification; it undergoes increased strain due to asymmetrical leaflet geometry. This investigation presents the mechanisms in which cyclic stretch affects inflammatory and osteogenic pathways of aortic valve disease. We show that human aortic valve interstitial cells (AVICs) exposed to stretch express increased matrix metalloproteinases (MMPs) and interleukins (ILs), activate macrophages, and upregulate family members in the transforming growth factor beta (TGF[Beta]) signaling cascade. Multiple microRNAs are implicated to modulate aortic valve disease. Analysis of the miRNA-Sequencing data found miR-148a to be repressed by stretch and target inhibitor of kappa light polypeptide gene enhancer in B cells (IKBKB), an activator of the nuclear factor kappa light chain enhancer of activated B cells (NF-[kappa]B) signaling pathway of inflammation. MiR -148a mimic transfection in AVICs repressed IKBKB and downstream NF-[kappa]B signaling at both transcriptional and translational contexts. We additionally identified decreased miR-19b expression in stretched AVICs and bicuspid aortic valve tissue. Transfection with miR-19b mimic decreased transcription of potential targets, transforming growth factor beta receptor II (TGFBR2) and insulin-like growth factor 1 (IGF-1); however, alkaline phosphatase was simultaneously upregulated indicating that stretch responsive miR-19b may influence valve calcification in an alternative pathway. Further investigation of IGF-1 is necessary. Development of microRNA based treatments for aortic valve disease may circumvent the limited therapeutic options currently available

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