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Published on: February 13, 2019
Cardiomyocyte-Specific Wt1 Is Involved in Cardiac Metabolism and Response to Damage
Sandra Díaz Del Moral1, Maha Benaouicha2, Cristina Villa Del Campo3,4
1Department of Animal Biology, Faculty of Science, University of Málaga, 29071 Málaga, Spain.
Abstract:
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 αMHCMerCreMer 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.
Insights
The Wilms tumor suppressor gene (Wt1) plays a crucial role in heart health. Loss of WT1 in adult cardiomyocytes leads to cardiac damage and dysfunction, highlighting its protective function.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Gene Regulation
Background:
- The Wilms tumor suppressor gene (Wt1) encodes a transcription factor vital for organ development, including the heart.
- Transient and low-level WT1 expression is observed in embryonic and adult cardiomyocytes, respectively.
Purpose of the Study:
- To investigate the function of WT1 in maintaining cardiac homeostasis.
- To determine WT1's role in the response of cardiomyocytes to pharmacological damage.
Main Methods:
- Silencing of Wt1 in cultured neonatal murine cardiomyocytes.
- Conditional ablation of WT1 in adult cardiomyocytes using αMHCMerCreMer and WT1-floxed mice.
- Assessment of cardiac function, metabolism, and response to doxorubicin.
Main Results:
- Wt1 silencing in neonatal cardiomyocytes altered mitochondrial membrane potential and calcium homeostasis gene expression.
- WT1 ablation in adult cardiomyocytes induced hypertrophy, fibrosis, metabolic changes, and mitochondrial dysfunction.
- Conditional WT1 deletion exacerbated doxorubicin-induced cardiac damage.
Conclusions:
- WT1 is essential for myocardial physiology and maintaining cardiac homeostasis.
- WT1 plays a protective role against cardiac damage, particularly in response to toxic insults.
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