title: Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3.
abstract: Calcific aortic valve disease (CAVD) is a major cause of morbidity in the aging population, but the underlying mechanisms of its progression remain poorly understood. Aortic valve calcification preferentially occurs on the fibrosa, which is subjected to disturbed flow. The side-specific progression of the disease is characterized by inflammation, calcific lesions, and extracellular matrix (ECM) degradation. Here, we explored the role of mechanosensitive microRNA-181b and its downstream targets in human aortic valve endothelial cells (HAVECs). Mechanistically, miR-181b is upregulated in OS and fibrosa, and it targets TIMP3, SIRT1, and GATA6, correlated with increased gelatinase/MMP activity. Overexpression of miR-181b led to decreased TIMP3 and exacerbated MMP activity as shown by gelatinase assay, and miR-181b inhibition decreased gelatinase activity through the repression of TIMP3 levels. Luciferase assay showed specific binding of miR-181b to the TIMP3 gene. Overexpression of miR-181b in HAVECs subjected to either LS or OS increased MMP activity, and miR-181b inhibition abrogated shear-sensitive MMP activity. These studies suggest that targeting this shear-dependent miRNA may provide a novel noninvasive treatment for CAVD.
authors.affiliation: Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Jack M
authors.initials: JM
authors.lastname: Heath
authors.affiliation: Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Fernandez Esmerats
authors.affiliation: Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Lucky
authors.initials: L
authors.lastname: Khambouneheuang
authors.affiliation: Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Simmons
authors.affiliation: Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA. hanjoong.jo@bme.gatech.edu.|Department of Cardiology, Emory University, Atlanta, GA, USA. hanjoong.jo@bme.gatech.edu.
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
mesh_terms: D020413:3' Untranslated Regions; D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology; D001665:Binding Sites; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006349:Heart Valve Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D040542:Mechanotransduction, Cellular; D035683:MicroRNAs / Q000235:genetics; D013314:Stress, Mechanical; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C000608460:MIRN-181 microRNA, human; D035683:MicroRNAs; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D018093:Gelatinases
keywords: Aortic valve; Endothelium; Extracellular matrix; Matrix metalloproteinase; Shear stress; microRNA