MicroRNA-144 dysregulates the transforming growth factor-β signaling cascade and contributes to the development of bronchiolitis obliterans syndrome after human lung transplantation

Zhongping Xu, Sabarinathan Ramachandran, Muthukumar Gunasekaran, Fangyu Zhou, Elbert Trulock, Daniel Kreisel, Ramsey Hachem, Thalachallour Mohanakumar

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31 Scopus citations

Abstract

Background Bronchiolitis obliterans syndrome (BOS), chronic lung allograft rejection, remains an impediment for the function of the transplanted organ. In this study, we defined the role of the microRNA (miRNA) miR-144 in fibroproliferation leading to BOS. Methods Biopsy specimens were obtained from 20 lung transplant recipients with BOS(+) and 19 without BOS(-). Expression of miR-144 and its target, transforming growth factor-β (TGF-β)-induced factor homeobox 1(TGIF1), were analyzed by real-time polymerase chain reaction and Western blot. Overexpression of miR-144 and luciferase reporter genes were performed to elucidate miRNA-target interactions. The function of miR-144 was evaluated by transfecting fibroblasts and determining the response to TGF-β by analyzing Sma- and Mad-related family (Smads), fibroblast growth factor, TGF-β, and vascular endothelial growth factor. Smooth muscle actin-α-positive stress fibers and F-actin filaments in lung fibroblasts were analyzed by immunofluorescence. Results Analysis of miR-144 in the biopsy specimens demonstrated 4.1 ± 0.8-fold increases in BOS+ compared with BOS- patients, with a significant reduction in TGIF1 (3.6 ± 1.2-fold), a corepressor of Smads. In vitro transfection confirmed that over-expression of miR-144 results in a reduction in TGIF1 and an increase in SMAD2, SMAD4, fibroblast growth factor-6, TGF-β, and vascular endothelial growth factor. Increasing miR-144 by transfecting, increased smooth muscle actin-α and fibronectin, and knockdown of miR-144 diminished fibrogenesis in MRC-5 fibroblasts. Conclusions miR-144 is a critical regulator of the TGF-β signaling cascade and is over-expressed in lungs with BOS. Therefore, miR-144 is a potential target toward preventing fibrosis leading to BOS after lung transplant.

Original languageEnglish (US)
Article number6002
Pages (from-to)1154-1162
Number of pages9
JournalJournal of Heart and Lung Transplantation
Volume34
Issue number9
DOIs
StatePublished - Sep 1 2015

Bibliographical note

Funding Information:
Funding for these studies was provided by the National Institutes of Health grant RO1-HL0-56643-13 (T.M.) and the BJC Foundation (T.M.).

Keywords

  • TGF-β
  • bronchiolitis obliterans syndrome
  • lung transplantation
  • microRNA

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