Journal Article

Fra-2 mediates oxygen-sensitive induction of transforming growth factor β in cardiac fibroblasts

Sashwati Roy, Savita Khanna, Ali Azad, Rebecca Schnitt, Guanglong He, Cora Weigert, Hidenori Ichijo and Chandan K. Sen

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 87, issue 4, pages 647-655
Published in print September 2010 | ISSN: 0008-6363
Published online April 2010 | e-ISSN: 1755-3245 | DOI:

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In the ischaemia-reperfused heart, transforming growth factor β (TGFβ) 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 TGFβ. Here, we sought to characterize the molecular mechanisms responsible for the O2-sensitive transcriptional induction of TGFβ 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 TGFβ were induced in the CF-rich peri-infarct tissue as well as in CF exposed to hyperoxic challenge. Reporter studies demonstrated that TGFβ transcription is hyperoxia inducible. Deletion of any one or both of the activating protein-1 (AP-1) binding sites in the TGFβ reporter construct resulted in loss of O2 sensitivity, demonstrating that AP-1 confers O2 sensitivity to TGFβ 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 O2-sensitive TGFβ transcription. Knockdown of Fra-2 significantly blunted O2-induced expression of TGFβ1 as well as TGFβ3 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 O2-inducible AP-1 activation and induction of TGFβ.


Taken together with the observation that Fra-2-regulated genes are implicated in fibrosis, identification of Fra-2 as an O2-sensitive transcriptional regulator of inducible TGFβ expression positions Fra-2 as an important player in reoxygenation-induced fibrosis.

Keywords: Oxygen; Reperfusion; TGF

Journal Article.  5088 words.  Illustrated.

Subjects: Cardiovascular Medicine