Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
Department of Cardiovascular Research and.
JCI Insight. 2019 Jul 16;5(15):126721. doi: 10.1172/jci.insight.126721.
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.
纤维化瘢痕导致心肌梗死后心力衰竭的进展。因此，开发特异性的治疗方案来对抗纤维化具有重要的临床意义。转录因子 SOX9 在胚胎发生过程中起重要的调节作用，但最近的数据表明其在器官纤维化中还具有因果作用。我们在这里表明，SOX9 在小鼠心肌梗死后的瘢痕中上调。成纤维细胞特异性的 Sox9 缺失改善了 MI 诱导的体内左心室功能障碍、扩张和心肌瘢痕形成。出乎意料的是，Sox9 的缺失也强烈消除了 MI 后慢性期瘢痕中持续存在的白细胞浸润。来自梗死瘢痕的 RNA 测序显示，成纤维细胞中 Sox9 的缺失导致与细胞外基质、蛋白水解和炎症相关的基因表达显著下调。重要的是，体外分离的心脏成纤维细胞中 Sox9 的缺失也影响了基因表达，与心脏瘢痕相似，并降低了成纤维细胞的增殖、迁移和收缩能力。总之，我们的数据表明，成纤维细胞 SOX9 是心脏纤维化和炎症的主要调节因子，可能是 MI 期间的一个新的治疗靶点。
