Department of Internal Medicine and Cardiology, University Hospital, TU Dresden, Germany.
Department of Internal Medicine and Cardiology, University Hospital, TU Dresden, Germany.
Int J Cardiol. 2019 May 1;282:68-75. doi: 10.1016/j.ijcard.2019.01.078. Epub 2019 Feb 2.
The transcription factor Sox9 has been associated with cardiac injury and remodeling. Studies of mammalian hearts confirm Sox9 upregulation in fibroblasts following ischemic insults associated with enhanced fibrosis. The role of cardiomyocyte-specific Sox9 remains unclear. This study aimed to evaluate the role of cardiomyocyte-specific Sox9 in development and progression of left ventricular (LV) hypertrophy and fibrosis.
In male conditional Sox9 knockout mice (Sox9-KO) or floxed littermates (control group) transverse aortic constriction (TAC) was performed to induce LV hypertrophy. LV function and wall thickness were assessed weekly using echocardiography. LV mRNA- and protein expression levels of hypertrophy-, fibrosis-, and remodeling-associated genes were analyzed for each time point. Histological sections were stained for fibrosis and Sox9 expression.
Only one week after TAC, the control group showed significantly enhanced heart weights and thickened LV posterior walls accompanied by elevated Anp- and Lox-mRNA levels. Simultaneously, Col1a1- and Col3a1-levels as well as Sox9 expression were strongly upregulated, Contrary, Sox9-KO mice did not develop cardiac hypertrophy until 4 weeks after TAC. Collagen and Sox9 expression also peaked at that later time point. Ejection fraction declined similarly in both groups after TAC. However, the control group showed a slightly better cardiac performance at 2 weeks after TAC.
Cardiomyocyte-specific Sox9 mediates hypertrophy and early fibrosis, following cardiac pressure-overload. Loss of Sox9 delays cardiac growth and remodeling processes, however, does not preserve the cardiac function. We suggest that cardiomyocyte-driven Sox9 initiates a pro-hypertrophic cascade, possibly involving a cross-talk between myocytes and fibroblasts.
转录因子 Sox9 与心脏损伤和重塑有关。哺乳动物心脏的研究证实，缺血性损伤后成纤维细胞 Sox9 上调，纤维化增强。心肌细胞特异性 Sox9 的作用尚不清楚。本研究旨在评估心肌细胞特异性 Sox9 在左心室（LV）肥厚和纤维化的发展和进展中的作用。
在雄性条件性 Sox9 敲除小鼠（Sox9-KO）或 floxed 同窝仔鼠（对照组）中进行横主动脉缩窄（TAC）以诱导 LV 肥厚。每周使用超声心动图评估 LV 功能和壁厚度。分析每个时间点与肥厚、纤维化和重塑相关基因的 LV mRNA 和蛋白表达水平。对纤维化和 Sox9 表达进行组织学染色。
仅在 TAC 后 1 周，对照组的心脏重量显著增加，LV 后壁增厚，同时 Anp-和 LoxmRNA 水平升高。同时，Col1a1-和 Col3a1 水平以及 Sox9 表达也被强烈上调。相反，Sox9-KO 小鼠在 TAC 后 4 周才发生心脏肥厚。胶原和 Sox9 表达也在该时间点达到峰值。TAC 后两组的射血分数均相似下降。然而，对照组在 TAC 后 2 周的心脏功能略好。
心肌细胞特异性 Sox9 介导心脏压力超负荷后的肥厚和早期纤维化。Sox9 的缺失延迟了心脏生长和重塑过程，但不能维持心脏功能。我们认为，心肌细胞驱动的 Sox9 启动了一个促肥厚级联反应，可能涉及心肌细胞和成纤维细胞之间的交叉对话。
