Cardiac fibroblasts are a major source of cardiac fibrosis during heart repair processes in various heart diseases. Although it has been shown that cardiac fibroblasts become senescent in response to heart injury, it is unknown how the senescence of cardiac fibroblasts is regulated
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Cardiac fibroblasts are a major source of cardiac fibrosis during heart repair processes in various heart diseases. Although it has been shown that cardiac fibroblasts become senescent in response to heart injury, it is unknown how the senescence of cardiac fibroblasts is regulated in vivo.
Gata4, a cardiogenic transcription factor essential for heart development, is also expressed in cardiac fibroblasts. However, it remains elusive about the role of Gata4 in cardiac fibroblasts. To define the role of Gata4 in cardiac fibroblasts, we generated cardiac fibroblast-specific
Gata4 knockout mice by cross-breeding
Tcf21-MerCreMer mice with
Gata4fl/fl mice. Using this mouse model, we could genetically ablate
Gata4 in Tcf21 positive cardiac fibroblasts in an inducible manner upon tamoxifen administration. We found that cardiac fibroblast-specific deletion of
Gata4 spontaneously induces senescence in cardiac fibroblasts in vivo and in vitro. We also found that Gata4 expression in both cardiomyocytes and non-myocytes significantly decreases in the aged heart. Interestingly, when
αMHC-MerCreMer mice were bred with
Gata4fl/fl mice to generate cardiomyocyte-specific Gata4 knockout mice, no senescent cells were detected in the hearts. Taken together, our results demonstrate that
Gata4 deficiency in cardiac fibroblasts activates a program of cellular senescence, suggesting a novel molecular mechanism of cardiac fibroblast senescence.
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