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miR-199a-5p Is Upregulated during Fibrogenic Response to Tissue Injury and Mediates TGFbeta-Induced Lung Fibroblast Activation by Targeting Caveolin-1

Lino Cardenas, CL and Henaoui, IS and Courcot, E and Roderburg, C and Cauffiez, C and Aubert, S and Copin, MC and Wallaert, B and Glowacki, F and Dewaeles, E and Milosevic, J and Maurizio, J and Tedrow, J and Marcet, B and Lo-Guidice, JM and Kaminski, N and Barbry, P and Luedde, T and Perrais, M and Mari, B and Pottier, N (2013) miR-199a-5p Is Upregulated during Fibrogenic Response to Tissue Injury and Mediates TGFbeta-Induced Lung Fibroblast Activation by Targeting Caveolin-1. PLoS Genetics, 9 (2). ISSN 1553-7390

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Abstract

As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases. © 2013 Lino Cardenas et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lino Cardenas, CL
Henaoui, IS
Courcot, E
Roderburg, C
Cauffiez, C
Aubert, S
Copin, MC
Wallaert, B
Glowacki, F
Dewaeles, E
Milosevic, J
Maurizio, J
Tedrow, Jjrt45@pitt.eduJRT45
Marcet, B
Lo-Guidice, JM
Kaminski, N
Barbry, P
Luedde, T
Perrais, M
Mari, B
Pottier, N
Date: 1 February 2013
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 9
Number: 2
DOI or Unique Handle: 10.1371/journal.pgen.1003291
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
ISSN: 1553-7390
Other ID: NLM PMC3573122
PubMed Central ID: PMC3573122
PubMed ID: 23459460
Date Deposited: 20 Mar 2013 20:44
Last Modified: 27 Jan 2019 02:55
URI: http://d-scholarship.pitt.edu/id/eprint/17834

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