Impact of Cellular Senescence on Age-Related Myocardial Dysfunction: A Molecular Imaging Approach
Abstract
Epidemiologic evidence shows alteration of myocardial properties with age resulting in progressive decline in diastolic function. The presence of a population of senescent cardiomyocytes and the soluble factors they secrete (senescence-associated secretory phenotype) could be a major player in the progressive deterioration of myocardial function observed during aging. To test this hypothesis, we propose 1) to generate a new model of cardiac-specific inducible senescence and evaluate cardiac function in association with cellular senescence and 2) to develop a method for in vivo imaging of cellular senescence. The animal model of expected to develop cardiac-specific senescence was generated by crossing mice with cardiac-MerCreMer) with enhancer of zeste homolog 2-floxed mice (Ezh2fl/fl), enabling tissue-specific conditional deletion of Ezh2, a key component of a protein complex involved in the repression of p16INK4a, a master regulator of cellular senescence. Tamoxifen treated double transgenic animals showed the presence of the recombined allele, marker of Ezh2 deletion, in heart tissue. The follow-up of the animals for up to 7 months after genomic recombination did not result in impaired cardiac function, as assessed by echocardiography. Histological evaluation did not show the presence of senescent cells in the heart tissue. The generation of malondialdehyde-vimentin, a marker reported to be expressed at the membrane of senescent cells, was unsuccessful. Murine cardiomyocytes were used to screen for alternative markers of cellular senescence. The absence of detectable cellular senescence in the generated animal model prevented the selection of a molecular target for tracer development with validated in vivo relevance for cardiac tissue, as initially anticipated.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2022
- Accession Number
- AD1170064
Entities
People
- Jakub Toczek
Organizations
- Yale University