Díaz Del Moral Sandra, Benaouicha Maha, Villa Del Campo Cristina, Torres Miguel, Wagner Nicole, Wagner Kay-Dietrich, Muñoz-Chápuli Ramón, Carmona Rita
Department of Animal Biology, Faculty of Science, University of Málaga, 29071 Málaga, Spain.
Department of Cell Biology, Genetics and Physiology, Faculty of Science, University of Málaga, 29071 Málaga, Spain.
J Cardiovasc Dev Dis. 2023 May 12;10(5):211. doi: 10.3390/jcdd10050211.
The Wilms tumor suppressor gene (Wt1) encodes a C2H2-type zinc-finger transcription factor that participates in transcriptional regulation, RNA metabolism, and protein-protein interactions. WT1 is involved in the development of several organs, including the kidneys and gonads, heart, spleen, adrenal glands, liver, diaphragm, and neuronal system. We previously provided evidence of transient WT1 expression in about 25% of cardiomyocytes of mouse embryos. Conditional deletion of Wt1 in the cardiac troponin T lineage caused abnormal cardiac development. A low expression of WT1 has also been reported in adult cardiomyocytes. Therefore, we aimed to explore its function in cardiac homeostasis and in the response to pharmacologically induced damage. Silencing of Wt1 in cultured neonatal murine cardiomyocytes provoked alterations in mitochondrial membrane potential and changes in the expression of genes related to calcium homeostasis. Ablation of WT1 in adult cardiomyocytes by crossing αMHC mice with homozygous WT1-floxed mice induced hypertrophy, interstitial fibrosis, altered metabolism, and mitochondrial dysfunction. In addition, conditional deletion of WT1 in adult cardiomyocytes increased doxorubicin-induced damage. These findings suggest a novel role of WT1 in myocardial physiology and protection against damage.
威尔姆斯肿瘤抑制基因（Wt1）编码一种C2H2型锌指转录因子，该因子参与转录调控、RNA代谢以及蛋白质-蛋白质相互作用。WT1参与多个器官的发育，包括肾脏、性腺、心脏、脾脏、肾上腺、肝脏、膈肌和神经系统。我们之前提供的证据表明，WT1在小鼠胚胎约25%的心肌细胞中短暂表达。在心肌肌钙蛋白T谱系中条件性缺失Wt1会导致心脏发育异常。也有报道称WT1在成年心肌细胞中低表达。因此，我们旨在探究其在心脏稳态以及对药物诱导损伤的反应中的功能。在培养的新生小鼠心肌细胞中沉默Wt1会引发线粒体膜电位改变以及与钙稳态相关基因表达的变化。通过将αMHC小鼠与纯合WT1-floxed小鼠杂交，在成年心肌细胞中敲除WT1会导致肥大、间质纤维化、代谢改变以及线粒体功能障碍。此外，成年心肌细胞中条件性缺失WT1会增加阿霉素诱导的损伤。这些发现表明WT1在心肌生理学和抗损伤保护中具有新的作用。
