Document Detail

Fra-2 mediates oxygen-sensitive induction of transforming growth factor beta in cardiac fibroblasts.
MedLine Citation:
PMID:  20427335     Owner:  NLM     Status:  MEDLINE    
AIMS: In the ischaemia-reperfused heart, transforming growth factor beta (TGFbeta) proteins trigger the differentiation of cardiac fibroblasts (CFs) contributing to fibrosis. Reoxygenation of the heart, in addition to being a trigger for reperfusion injury, induces tissue remodelling by hyperoxia-sensitive signalling processes involving TGFbeta. Here, we sought to characterize the molecular mechanisms responsible for the O(2)-sensitive transcriptional induction of TGFbeta in murine CF and to test the significance of such findings in the infarcted myocardium in vivo using laser capture microdissection.
METHODS AND RESULTS: All three isoforms of TGFbeta were induced in the CF-rich peri-infarct tissue as well as in CF exposed to hyperoxic challenge. Reporter studies demonstrated that TGFbeta transcription is hyperoxia inducible. Deletion of any one or both of the activating protein-1 (AP-1) binding sites in the TGFbeta reporter construct resulted in loss of O(2) sensitivity, demonstrating that AP-1 confers O(2) sensitivity to TGFbeta transcription. Fos-related AP-1 transcription factor (Fra-2) and Ask-1 (apoptosis signal-regulating kinase-1) were identified as key mediators of AP-1-dependent O(2)-sensitive TGFbeta transcription. Knockdown of Fra-2 significantly blunted O(2)-induced expression of TGFbeta1 as well as TGFbeta3 in CF. Knockdown of Ask-1 blunted hyperoxia-induced Fra-2 gene expression and nuclear localization in CF. Collectively, these observations point towards a central role of Ask-1 and Fra-2 in O(2)-inducible AP-1 activation and induction of TGFbeta.
CONCLUSION: Taken together with the observation that Fra-2-regulated genes are implicated in fibrosis, identification of Fra-2 as an O(2)-sensitive transcriptional regulator of inducible TGFbeta expression positions Fra-2 as an important player in reoxygenation-induced fibrosis.
Sashwati Roy; Savita Khanna; Ali Azad; Rebecca Schnitt; Guanglong He; Cora Weigert; Hidenori Ichijo; Chandan K Sen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-04-28
Journal Detail:
Title:  Cardiovascular research     Volume:  87     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-13     Completed Date:  2010-12-15     Revised Date:  2013-06-17    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  647-55     Citation Subset:  IM    
Department of Surgery, The Ohio State University Medical Center, 513 Davis Heart and Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210, USA.
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MeSH Terms
Binding Sites
Cells, Cultured
Disease Models, Animal
Fibroblasts / metabolism*,  pathology
Fos-Related Antigen-2 / genetics,  metabolism*
Hyperoxia / genetics,  metabolism*,  pathology
MAP Kinase Kinase Kinase 5 / metabolism
Mice, Inbred C57BL
Myocardial Infarction / genetics,  metabolism*,  pathology
Myocardial Reperfusion Injury / genetics,  metabolism*,  pathology
Myocardium / metabolism*,  pathology
Oxygen / metabolism*
Promoter Regions, Genetic
RNA Interference
Time Factors
Transcription Factor AP-1 / genetics
Transcription, Genetic
Transforming Growth Factor beta / genetics,  metabolism*
Transforming Growth Factor beta1 / metabolism
Transforming Growth Factor beta2 / metabolism
Transforming Growth Factor beta3 / metabolism
Grant Support
Reg. No./Substance:
0/Fos-Related Antigen-2; 0/Fosl2 protein, mouse; 0/Tgfb1 protein, mouse; 0/Tgfb2 protein, mouse; 0/Tgfb3 protein, mouse; 0/Transcription Factor AP-1; 0/Transforming Growth Factor beta; 0/Transforming Growth Factor beta1; 0/Transforming Growth Factor beta2; 0/Transforming Growth Factor beta3; 7782-44-7/Oxygen; EC Kinase Kinase Kinase 5; EC protein, mouse

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