Impact of diffused versus vasculature targeted DNA damage on the heart of mice depleted of telomeric factor Ft1

• Main Authors: La Torre, Mattia, Centofante, Eleonora, Nicoletti, Carmine, Burla, Romina, Giampietro, Alessandro, Cannistrà, Federica, Schirone, Leonardo, Valenti, Valentina, Sciarretta, Sebastiano, Musarò, Antonio, Saggio, Isabella
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2024
• Subjects: Medicine, Health and Life Sciences; Cardiomyopathy; DNA damage
• Online Access: https://hdl.handle.net/10356/173855
• Institution: Nanyang Technological University

DNA damage is emerging as a driver of heart disease, although the cascade of events, its timing, and the cell types involved are yet to be fully clarified. In this context, the implication of cardiomyocytes has been highlighted, while that of vasculature smooth muscle cells has been implicated but not explored exhaustively. In our previous work we characterized a factor called Ft1 in mice and AKTIP in humans whose depletion generates telomere instability and DNA damage. Herein, we explored the effect of the reduction of Ft1 on the heart with the goal of comparatively defining the impact of DNA damage targeted to vasculature smooth muscle cells to that of diffuse damage. Using two newly generated mouse models, Ft1 constitutively knocked out (Ft1ko) mice, and mice in which we targeted the Ft1 depletion to the smooth muscle cells (Ft1sm22ko), it is shown that both genetic models display cardiac defects but with differences. Both Ft1ko and Ft1sm22ko mice display hypertrophy, fibrosis, and functional heart defects. Interestingly, Ft1sm22ko mice have early milder pathological traits that become manifest with age. Significantly, the defects of Ft1ko mice, including the alteration of the left ventricle and functional heart defects, are rescued by depletion of the DNA damage sensor p53. These results point to Ft1 deficiency as a driver of cardiac disease and show that Ft1 deficiency targeted to vasculature smooth muscle cells generates a pre-pathological profile exacerbated by age.