title: Roles of transforming growth factor-β1 and OB-cadherin in porcine cardiac valve myofibroblast differentiation.
abstract: Calcific aortic stenosis is a common disease, and some of its early causes are the activation and differentiation of resident fibroblasts to myofibroblasts in response to transforming growth factor β1 (TGF-β1). The aim of this study was to understand how TGF-β1 and its downstream effector, OB-cadherin [cadherin 11 (CDH11)], regulate porcine myofibroblast phenotypes. Based on whole-genome microarrays, 95 and 107 genes are up- and down-regulated at both the early (8 h) and the late (24 h) time points of TGF-β1 treatment. Gene functions related to cell adhesion, skeletal system development, and extracellular matrix are up-regulated by TGF-β1, whereas oxidation-reduction and steroid metabolic process are down-regulated. Notably, one of the cell adhesion molecules, CDH11, is up-regulated by ∼2-fold through both the Smad2/3 and the ERK pathways elicited by TGF-β1. CDH11 mediates cell-cell contacts in both valvular fibroblasts and myofibroblasts. Knockdown of CDH11 by small interfering RNA increases the myofibroblast phenotype, including an ∼2-fold increase in α-smooth muscle actin (α-SMA) expression and stress fiber formation. In contrast, increased binding of CDH11 through antibody treatment inhibits α-SMA expression. This study presents gene functional changes in response to TGF-β1 at the systems level and supports an inhibitory role of CDH11 in myofibroblast differentiation.
authors.affiliation: Department of Chemical and Biological Engineering, Department of Molecular, Cellular and Developmental Biology, BioFrontiers Institute, and.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, BioFrontiers Institute, and.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Leinwand
authors.affiliation: Department of Chemical and Biological Engineering, BioFrontiers Institute, and Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado, USA kristi.anseth@colorado.edu.
authors.forename: Kristi S
authors.initials: KS
authors.lastname: Anseth
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002454:Cell Differentiation; D020869:Gene Expression Profiling; D006351:Heart Valves / Q000166:cytology / Q000378:metabolism*; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013552:Swine; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D000199:Actins; D015820:Cadherins; D016212:Transforming Growth Factor beta; C086960:osteoblast cadherin
keywords: aortic valve fibrosis; genome-wide transcription; α-smooth muscle actin