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Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation
- Source :
- JCI Insight. 4
- Publication Year :
- 2019
- Publisher :
- American Society for Clinical Investigation, 2019.
-
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.
- Subjects :
- 0301 basic medicine
Cardiac fibrosis
Myocardial Infarction
Down-Regulation
Inflammation
Extracellular matrix
Cicatrix
Mice
Ventricular Dysfunction, Left
03 medical and health sciences
0302 clinical medicine
Cell Movement
Fibrosis
Myocardial scarring
Leukocytes
medicine
Animals
RNA-Seq
Myocardial infarction
Fibroblast
Cell Proliferation
Mice, Knockout
business.industry
Myocardium
General Medicine
Fibroblasts
medicine.disease
Extracellular Matrix
030104 developmental biology
medicine.anatomical_structure
Gene Expression Regulation
030220 oncology & carcinogenesis
Heart failure
Proteolysis
Cancer research
medicine.symptom
business
Research Article
Subjects
Details
- ISSN :
- 23793708
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- JCI Insight
- Accession number :
- edsair.doi.dedup.....6e3a8a2cc42f7880f34abda69f7065aa