title: 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.
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.
authors: *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.
authors: Vishal
authors: V
authors: Patel
authors: *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.
authors: Katrina
authors: K
authors: Carrion
authors: *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.
authors: Andrew
authors: A
authors: Hollands
authors: *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.
authors: Andrew
authors: A
authors: Hinton
authors: *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.
authors: Thomas
authors: T
authors: Gallegos
authors: *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.
authors: Jeffrey
authors: J
authors: Dyo
authors: *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.
authors: Roman
authors: R
authors: Sasik
authors: *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.
authors: Emma
authors: E
authors: Leire
authors: *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.
authors: Gary
authors: G
authors: Hardiman
authors: *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.
authors: Salah A
authors: SA
authors: Mohamed
authors: *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.
authors: Sanjay
authors: S
authors: Nigam
authors: *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.
authors: Charles C
authors: CC
authors: King
authors: *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.
authors: Victor
authors: V
authors: Nizet
authors: *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.
authors: Vishal
authors: V
authors: Nigam
mesh_terms: D001021:Aortic Valve / Q000002:abnormalities* / Q000276:immunology / Q000378:metabolism; D000082882:Bicuspid Aortic Valve Disease; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D006349:Heart Valve Diseases / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological
chemical_list: D015415:Biomarkers; C550570:MIRN148 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D012333:RNA, Messenger; D051550:I-kappa B Kinase; C496560:IKBKB protein, human
keywords: aortic valve calcification; inflammation; mechanotransduction
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