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Roles of transforming growth factor-?1 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 ?1 (TGF-?1). The aim of this study was to understand how TGF-?1 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-?1 treatment. Gene functions related to cell adhesion, skeletal system development, and extracellular matrix are up-regulated by TGF-?1, 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-?1. 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 ?-smooth muscle actin (?-SMA) expression and stress fiber formation. In contrast, increased binding of CDH11 through antibody treatment inhibits ?-SMA expression. This study presents gene functional changes in response to TGF-?1 at the systems level and supports an inhibitory role of CDH11 in myofibroblast differentiation.

SUBMITTER: Wang H

PROVIDER: S-EPMC4202096 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Roles of transforming growth factor-β1 and OB-cadherin in porcine cardiac valve myofibroblast differentiation.

Wang Huan H Leinwand Leslie A LA Anseth Kristi S KS

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20140709 10

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 poi ...[more]

PMID: 25008089

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Project description:Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with irreversible loss of lung tissue and function. Myofibroblasts in the lung are key cellular mediators of IPF progression. Transforming growth factor (TGF)-β1, a major profibrogenic cytokine, induces pulmonary myofibroblast differentiation, and emerging evidence has established the importance of microRNAs (miRs) in the development of IPF. The objective of this study was to define the pro-fibrotic roles and mechanisms of miRs in TGF-β1-induced pulmonary myofibroblast differentiation. Using RNA sequencing, we identified miR-424 as an important TGF-β1-induced miR in human lung fibroblasts (HLFs). Quantitative RT-PCR confirmed that miR-424 expression was increased by 2.6-fold in HLFs in response to TGF-β1 and was 1.7-fold higher in human fibrotic lung tissues as compared to non-fibrotic lung tissues. TGF-β1-induced upregulation of miR-424 was blocked by the Smad3 inhibitor SIS3, suggesting the involvement of this canonical TGF-β1 signaling pathway. Transfection of a miR-424 hairpin inhibitor into HLFs reduced TGF-β1-induced expression of classic myofibroblast differentiation markers including ɑ-smooth muscle actin (ɑ-SMA) and connective tissue growth factor (CTGF), whereas a miR-424 mimic significantly enhanced TGF-β1-induced myofibroblast differentiation. In addition, TGF-β1 induced Smad3 phosphorylation in HLFs, and this response was reduced by the miR-424 inhibitor. In silico analysis identified Slit2, a protein that inhibits TGF-β1 profibrogenic signaling, as a putative target of regulation by miR-424. Slit2 is less highly expressed in human fibrotic lung tissues than in non-fibrotic lung tissues, and knockdown of Slit2 by its siRNA enhanced TGF-β1-induced HLF differentiation. Overexpression of a miR-424 mimic down-regulated expression of Slit2 but not the Slit2 major receptor ROBO1 in HLFs. Luciferase reporter assays showed that the miR-424 mimic represses Slit2 3' untranslated region (3'-UTR) reporter activity, and mutations at the seeding regions in the 3'-UTR of Slit2 abolish this inhibition. Together, these data demonstrate a pro-fibrotic role of miR-424 in TGF-β1-induced HLF differentiation. It functions as a positive feed-back regulator of the TGF-β1 signaling pathway by reducing expression of the negative regulator Slit2. Thus, targeting miR-424 may provide a new therapeutic strategy to prevent myofibroblast differentiation and IPF progression.

Dataset Information

Roles of transforming growth factor-?1 and OB-cadherin in porcine cardiac valve myofibroblast differentiation.

Publications

Roles of transforming growth factor-β1 and OB-cadherin in porcine cardiac valve myofibroblast differentiation.

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