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Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation

Lookup NU author(s): Dr Ralf Kist

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Society for Clinical Investigation, 2019.

For re-use rights please refer to the publisher's terms and conditions.


Abstract

Fibrotic scarring drives the progression of heart failure after myocardial infarction (MI). Therefore, the development of specific treatment regimens to counteract fibrosis is of high clinical relevance. The transcription factor SOX9 functions as an important regulator during embryogenesis, but recent data point towards an additional causal role in organ fibrosis. We show here that SOX9 is upregulated in the scar after MI in mice. Fibroblast specific deletion of Sox9 ameliorated MI-induced left ventricular dysfunction, dilatation and myocardial scarring in vivo. Unexpectedly, deletion of Sox9 also potently eliminated persisting leukocyte infiltration of the scar in the chronic phase after MI. RNA-sequencing from the infarct scar revealed that Sox9 deletion in fibroblasts resulted in strongly downregulated expression of genes related to extracellular matrix, proteolysis and inflammation. Importantly, Sox9 deletion in isolated cardiac fibroblasts in vitro similarly affected gene expression as in the cardiac scar and reduced fibroblast proliferation, migration and contraction capacity. Together, our data demonstrate that fibroblast SOX9 functions as a master regulator of cardiac fibrosis and inflammation and might constitute a novel therapeutic target during MI.


Publication metadata

Author(s): Scharf GM, Kilian K, Cordero J, Wang Y, Grund A, Hofmann M, Froese N, Wang X, Kispert A, Kist R, Conway SJ, Geffers R, Wollert KC, Dobreva G, Bauersachs J, Heineke J

Publication type: Article

Publication status: Published

Journal: JCI Insight

Year: 2019

Volume: 4

Issue: 15

Pages: e126721

Print publication date: 08/08/2019

Online publication date: 16/07/2019

Acceptance date: 11/07/2019

Date deposited: 23/07/2019

ISSN (print): 2379-3708

Publisher: American Society for Clinical Investigation

URL: https://doi.org/10.1172/jci.insight.126721

DOI: 10.1172/jci.insight.126721

PubMed id: 31310588


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