GSE132265
Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation in mice after myocardial infarction
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 prevented their activation and myofibroblast differentiation. 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. Overall design: 10 weeks old mice, LAD was performed in Sox9 fl/fl and Sox9 fl/Per_cre mice. The Per_cre allow the deletion of Sox9 only in fibroblast cells. After 6 weeks. Scar tissue from both conditions were taken. 3 replicates in the control group and 3 replicates with Sox9-deletion. Total RNA was isolated for polyA RNA-seq.