Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation

Gesine M. Scharf, Katja Kilian, Julio Cordero, Yong Wang, Andrea Grund, Melanie Hofmann, Natali Froese, Xue Wang, Andreas Kispert, Ralf Kist, Simon Conway, Robert Geffers, Kai C. Wollert, Gergana Dobreva, Johann Bauersachs, Joerg Heineke

Research output: Contribution to journalArticle

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 sex-determining region Y box 9 (SOX9) functions as an important regulator during embryogenesis, but recent data point toward 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-Seq 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.

Original languageEnglish (US)
Article numbere126721
JournalJCI Insight
Volume4
Issue number15
DOIs
StatePublished - Aug 8 2019

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Cicatrix
Fibrosis
Fibroblasts
Inflammation
Myocardial Infarction
Gene Expression
Left Ventricular Dysfunction
Proteolysis
Embryonic Development
Extracellular Matrix
Dilatation
Leukocytes
Transcription Factors
Down-Regulation
Heart Failure
RNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Scharf, G. M., Kilian, K., Cordero, J., Wang, Y., Grund, A., Hofmann, M., ... Heineke, J. (2019). Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation. JCI Insight, 4(15), [e126721]. https://doi.org/10.1172/jci.insight.126721

Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation. / Scharf, Gesine M.; Kilian, Katja; Cordero, Julio; Wang, Yong; Grund, Andrea; Hofmann, Melanie; Froese, Natali; Wang, Xue; Kispert, Andreas; Kist, Ralf; Conway, Simon; Geffers, Robert; Wollert, Kai C.; Dobreva, Gergana; Bauersachs, Johann; Heineke, Joerg.

In: JCI Insight, Vol. 4, No. 15, e126721, 08.08.2019.

Research output: Contribution to journalArticle

Scharf, GM, Kilian, K, Cordero, J, Wang, Y, Grund, A, Hofmann, M, Froese, N, Wang, X, Kispert, A, Kist, R, Conway, S, Geffers, R, Wollert, KC, Dobreva, G, Bauersachs, J & Heineke, J 2019, 'Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation', JCI Insight, vol. 4, no. 15, e126721. https://doi.org/10.1172/jci.insight.126721
Scharf GM, Kilian K, Cordero J, Wang Y, Grund A, Hofmann M et al. Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation. JCI Insight. 2019 Aug 8;4(15). e126721. https://doi.org/10.1172/jci.insight.126721
Scharf, Gesine M. ; Kilian, Katja ; Cordero, Julio ; Wang, Yong ; Grund, Andrea ; Hofmann, Melanie ; Froese, Natali ; Wang, Xue ; Kispert, Andreas ; Kist, Ralf ; Conway, Simon ; Geffers, Robert ; Wollert, Kai C. ; Dobreva, Gergana ; Bauersachs, Johann ; Heineke, Joerg. / Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation. In: JCI Insight. 2019 ; Vol. 4, No. 15.
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