ArticleDisease models & mechanisms2013
Moderate and high amounts of tamoxifen in αMHC-MerCreMer mice induce a DNA damage response, leading to heart failure and death.
Article in Disease models & mechanisms, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers.
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Who cites it
114 citing papers in PubMed, 147 citations in OpenAlex.
- Local control of Cre-regulated genetic modeling in vivo using wireless implantable optoelectronics.Science advances · 2026Article
- Ckmm-Cre transgenic mice maintain phenotypic and cardiac mitochondrial homeostasis during ketogenic feeding.Molecular and cellular biochemistry · 2026Article
- Cardiomyocyte-specific depletion of integrin α3 preserves cardiac function after myocardial infarction.Basic research in cardiology · 2026Article
- Article
- Galectin-1 Is a Marker but Not a Mediator of Heart Failure With Preserved Ejection Fraction.Hypertension (Dallas, Tex. : 1979) · 2026Article
- Restoration of RBM22 overcomes the transcriptional and epigenetic barriers of cardiomyocyte proliferation for heart regeneration.Nature communications · 2026Article
- Activation of IRF3 in cardiomyocytes impairs mitochondrial oxidative function through PGC-1α inhibition and drives heart failure.Nature communications · 2026Article
- Activity of Cardiomyocyte Type 3 Deiodinase After Myocardial Infarction Influences Cardiac Recovery in Females.Endocrinology · 2026Article
- Sustained HIF activation in adult cardiomyocytes show transient beneficial effect in murine HFpEF model.European heart journal open · 2026Article
- Some Basics on Innate Neuroimmunology for Nonspecialists.Neuroimmunomodulation · 2026Review
- Lifetime Deletion of Skeletal Muscle Keap1 Attenuates Aging-Induced Cardiac Dysfunction via an Nrf2-Antioxidant Mechanism.Antioxidants (Basel, Switzerland) · 2025Article
- Cardiomyocyte cytosolic nuclear self-DNA contributes to the pathogenesis of desmoplakin cardiomyopathy.JCI insight · 2025Article
- TRPV2 mediates stress resilience in mouse cardiomyocytes.Communications biology · 2025Article
- α Protein Kinase 3 Is Essential for Neonatal and Adult Cardiac Function.Journal of the American Heart Association · 2025Article
- A Study on Potential Sources of Perineuronal Net-Associated Sema3A in Cerebellar Nuclei Reveals Toxicity of Non-Invasive AAV-Mediated Cre Expression in the Central Nervous System.International journal of molecular sciences · 2025Article
- Cre recombinase affects calcium dynamics already in young mice.Frontiers in pharmacology · 2025Article
- Metabolic phenotypes in a Lyz2Cre recombinase mouse model.Frontiers in immunology · 2025Article
- Cardiomyocyte Reduction of Hybrid/Complex N-Glycosylation in the Adult Causes Heart Failure With Reduced Ejection Fraction in the Absence of Cellular Remodeling.Journal of the American Heart Association · 2024Article
- Cardiac NADNature cardiovascular research · 2024Article
- Refined tamoxifen administration in mice by encouraging voluntary consumption of palatable formulations.Lab animal · 2024Article
54 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Numerous mouse models have utilized Cre-loxP technology to modify gene expression. Adverse effects of Cre recombinase activity have been reported, including in the heart. However, the mechanisms associated with cardiac Cre toxicity are largely unknown. Here, we show that expression of Cre in cardiomyocytes induces a DNA damage response, resulting in cardiomyocyte apoptosis, cardiac fibrosis and cardiac dysfunction. In an effort to increase the recombination efficiency of a widely used tamoxifen-sensitive Cre transgene under control of the α-myosin-heavy-chain promoter (αMHC-MerCreMer), we observed myocardial dysfunction and decreased survival, which were dependent on the dose of tamoxifen injected. After excluding a Cre-independent contribution by tamoxifen, we found that Cre induced myocardial fibrosis, activation of pro-fibrotic genes and cardiomyocyte apoptosis. Examination of the molecular mechanisms showed activation of DNA damage response signaling and p53 stabilization in the absence of loxP sites, suggesting that Cre induced illegitimate DNA breaks. Cardiomyocyte apoptosis was also induced by expressing Cre using adenoviral transduction, indicating that the effect was not dependent on genomic integration of the transgene. Cre-mediated homologous recombination at loxP sites was dose-dependent and had a ceiling effect at ∼80% of cardiomyocytes showing recombination. By titrating the amount of tamoxifen to maximize recombination while minimizing animal lethality, we determined that 30 μg tamoxifen/g body weight/day injected on three consecutive days is the optimal condition for the αMHC-MerCreMer system to induce recombination in the Rosa26-lacZ strain. Our results further highlight the importance of experimental design, including the use of appropriate genetic controls for Cre expression.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.