Abstract 20201: Activation of DNA Damage Response and Cellular Senescence in Cardiac Fibroblasts Limit Cardiac Fibrosis After Myocardial Infarction

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Abstract

Introduction: Activation and proliferation of cardiac fibroblasts (CFs) play an important role in the formation of cardiac fibrosis after myocardial infarction (MI). Molecular mechanisms that promote these are well studied and considered as therapeutic targets for preventing excessive cardiac fibrosis. However, the molecular mechanisms by which the activation of CFs is “extinguished” and returns to inactive, non-proliferative state after MI remain unclear. Recent reports suggest that activation of DNA damage response (DDR) and cellular senescence in CFs limits fibrosis of various tissues.

Methods and Results: We generated a mice model of MI and found that the number of proliferating CFs was increased up to day 4 but gradually decreased and returned to the basal level at day 7 after MI. In contrast, the number of the CFs positive for γH2AX, an active DDR marker, and senescence-associated beta-galactosidase-positive CFs were increased up to day 7 after MI, suggesting that cellular senescence occurred in CFs at day 5-7 after MI. To test the role of DDR and cellular senescence in cardiac fibrosis, we next established an in vitro model of senescent CFs by gamma-irradiation. Co-culture of senescent CFs and non-senescent CFs revealed that senescent CFs suppress the proliferation of the surrounding non-senescent CFs not in a paracrine manner but in a contact-dependent manner. We finally generated ATM heterozygote mice to partially block DDR and prevent cellular senescence. Following MI, CFs of ATM heterozygote mice remained proliferative even after day 7 and cardiac fibrosis was aggravated compared with wild-type mice.

Conclusions: Activation of DDR and cellular senescence in CFs limits cardiac fibrosis after MI through suppressing the proliferation not only of themselves but also of the surrounding non-senescent CFs. Regulation of cellular senescence in CFs may become one of the therapeutic strategies for preventing cardiac remodeling after MI.

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