Impact of diffused vs vasculature targeted DNA damage on the heart of mice depleted of the telomeric factor Ft1
DNA damage is emerging as driver of heart disease, however, 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 suggested, but not explored exhaustively. In our previous work we characterized a factor named Ft1 in mice and AKTIP in humans whose depletion generates telomere instability and DNA damage. Here, 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 smooth muscle cells to that of diffused 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), we show that both genetic models display cardiac defects but with differences. Both Ft1ko and Ft1sm22ko mice display hypertrophy and fibrosis, while only Ft1ko mice display a robust DNA damage response and cardiac left ventricle alterations. Interestingly, Ft1sm22ko mice have early pathological traits that become manifest with age. Significantly, the defects of Ft1ko mice, including the alteration of the left ventricle, are rescued by the 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. Overall design: Comparative gene expression profiling analysis of RNAseq data of cardiac tissue derived from WT, Ft1ko, Ft1sm22ko animals of 1 week of age.