Abstract 16067: miR-148a is a Novel Repressor of NF-kB Signaling in Aortic Valve Calcification
The purpose of this study was to identify novel modulators of the inflammatory pathways associated with aortic valve calcification. Bicuspid aortic valves (BAV) are at the highest risk of developing calcific disease. Bicuspid aortic valve leaflets experience increased stretch as compared to tricuspid aortic valves. We expose human aortic valve interstitial cells (AVICs) to cyclic stretch study the role of biomechanical stress in the pathogenesis of BAV calcification.
We have found that AVICs exposed to cyclic stretch have increased activation of inflammatory pathways including increased expression of interleukin (IL) and matrix metalloproteinase (MMP) genes. Since microRNAs (miRNAs) have important roles in regulating genes, miRNA-sequencing identified 33 miRNAs to be differentially regulated in response to stretch with a false discovery rate (FDR) <0.05. miR-148a is decreased by 48% in stretched AVICs with a FDR of 1.4x10-5. miR-148a levels are decreased by 58% in stretched AVICs by qPCR (p<0.01). miR-148a levels are decreased by 64% in human bicuspid aortic valve as compared to tricuspid aortic valve leaflets (p<0.005).
Since NF-κB signaling is activated in aortic valve calcification and regulates a number of the inflammatory genes activated in stretched AVICs, we examined if any of the stretch responsive miRNAs modulate NF-κB. In silico analysis predicts that miR-148a targets IKBKB, an activator of NF-κB. IKBKB expression is increased by 48% in stretched AVICs (p<0.005). AVICs transfected with miR-148a mimic have 62% less IKBKB mRNA (p<0.05). miR-148a decreases NF-κB activation and expression of ILs and MMPs in AVICs. This study presents novel data demonstrating that cyclic stretch is sufficient to activate inflammatory pathways in AVICs. The stretch repression of miRNA-148a results in increased expression of IKBKB. Increased IKBKB results in increased NF-κB signaling and inflammation.
The stretch activation of inflammatory pathways in AVICs and the miR-148a targeting of IKBKB have not been previously reported. Future studies will examine the potential of miR-148a l to treat and prevent aortic valve calcification and other cardiac diseases that involved activation of NF-κB signaling.
- © 2013 by American Heart Association, Inc.