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. Comparative gene expression profiling analysis of RNAseq data of cardiac tissue derived from WT, Ft1ko, Ft1sm22ko animals of 1 week of age.DNA损伤作为心血管疾病的致病驱动因素正逐渐受到关注，但其介导的级联反应、发生时序及所涉及的细胞类型尚未完全阐明。在此研究背景下，心肌细胞的致病作用已得到重点关注，而血管平滑肌细胞的潜在关联虽已被提出，但尚未得到全面深入的探索。在我们此前的研究中，我们对小鼠来源的Ft1因子与人类同源的AKTIP因子进行了功能鉴定，发现二者的缺失会引发端粒不稳定与DNA损伤。本研究探讨了Ft1表达下调对心脏的影响，旨在对比靶向平滑肌细胞的DNA损伤与弥散性DNA损伤的致病效应差异。本研究使用两种新构建的小鼠模型：Ft1全身敲除（Ft1ko）小鼠，以及将Ft1缺失靶向至平滑肌细胞的小鼠（Ft1sm22ko），实验结果显示两种基因工程模型均出现心脏缺陷，但二者存在显著差异。Ft1ko与Ft1sm22ko小鼠均表现出心肌肥厚与纤维化特征，但仅Ft1ko小鼠出现显著的DNA损伤应答与心脏左心室结构改变。值得注意的是，Ft1sm22ko小鼠存在早期病理特征，且这些特征会随年龄增长逐渐显现。尤为重要的是，通过敲除DNA损伤感应因子p53，可逆转Ft1ko小鼠的心脏缺陷，包括左心室结构异常。上述研究结果表明，Ft1缺失是心血管疾病的致病驱动因素，同时证实靶向血管平滑肌细胞的Ft1缺失会引发预病理状态，且该状态会随年龄增长而恶化。本研究对1周龄野生型（WT）、Ft1ko及Ft1sm22ko小鼠心脏组织的RNA测序（RNA-seq）数据进行了比较基因表达谱分析。