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FASEB J. 2015 May;29(5):1859-68. doi: 10.1096/fj.14-257808. Epub 2015 Jan 28.

The stretch responsive microRNA miR-148a-3p is a novel repressor of IKBKB, NF-κB signaling, and inflammatory gene expression in human aortic valve cells.

Author information

1
*Department of Pediatrics (Cardiology), Department of Pediatrics and School of Pharmacy, Pediatrics Diabetes Research Center, Departments of Pediatrics and Cellular and Molecular Medicine, and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Computational Science Research Center and Biomedical Informatics Research Center, San Diego State University, San Diego, California, USA; Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA; **Department of Cardiac Surgery, University Clinic of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany; and Rady Children's Hospital, San Diego, California, USA.
2
*Department of Pediatrics (Cardiology), Department of Pediatrics and School of Pharmacy, Pediatrics Diabetes Research Center, Departments of Pediatrics and Cellular and Molecular Medicine, and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Computational Science Research Center and Biomedical Informatics Research Center, San Diego State University, San Diego, California, USA; Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA; **Department of Cardiac Surgery, University Clinic of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany; and Rady Children's Hospital, San Diego, California, USA vnigam@ucsd.edu.

Abstract

Bicuspid aortic valves calcify at a significantly higher rate than normal aortic valves, a process that involves increased inflammation. Because we have previously found that bicuspid aortic valve experience greater stretch, we investigated the potential connection between stretch and inflammation in human aortic valve interstitial cells (AVICs). Microarray, quantitative PCR (qPCR), and protein assays performed on AVICs exposed to cyclic stretch showed that stretch was sufficient to increase expression of interleukin and metalloproteinase family members by more than 1.5-fold. Conditioned medium from stretched AVICs was sufficient to activate leukocytes. microRNA sequencing and qPCR experiments demonstrated that miR-148a-3p was repressed in both stretched AVICs (43% repression) and, as a clinical correlate, human bicuspid aortic valves (63% reduction). miR-148a-3p was found to be a novel repressor of IKBKB based on data from qPCR, luciferase, and Western blot experiments. Furthermore, increasing miR-148a-3p levels in AVICs was sufficient to decrease NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling and NF-κB target gene expression. Our data demonstrate that stretch-mediated activation of inflammatory pathways is at least partly the result of stretch-repression of miR-148a-3p and a consequent failure to repress IKBKB. To our knowledge, we are the first to report that cyclic stretch of human AVICs activates inflammatory genes in a tissue-autonomous manner via a microRNA that regulates a central inflammatory pathway.

KEYWORDS:

aortic valve calcification; inflammation; mechanotransduction

PMID:
25630970
PMCID:
PMC4771066
DOI:
10.1096/fj.14-257808
[Indexed for MEDLINE]
Free PMC Article

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