DNA Damage Accumulation Impedes Cardiac Repair After Myocardial Infarction Because of Insufficient IL-10 Expression

Abstract

DNA damage is strongly associated with myocardial infarction (MI), but its role in post-MI cardiac remodeling remains unclear. In this study, we investigated the effects of DNA double-strand breaks (DSBs), the most severe form of DNA damage, on cardiac remodeling using Ku80^+/− mice, which exhibit diminished expression of this key DSB repair protein. Ku80-deficient mice exhibited a worse prognosis, lower cardiac function, and a larger infarct size after MI than wild-type (WT) mice. Ku80-deficient mice also displayed persistent DSBs 2 weeks post-MI. Notably, Ku80-deficient mice had reduced anti-inflammatory M2 macrophage infiltration despite exhibiting no significant differences in bone marrow-derived macrophage polarization. In addition, the mRNA levels of interleukin-10 (IL-10), an anti-inflammatory cytokine essential for M2 macrophage polarization and infiltration, were significantly lower in Ku80-deficient hearts than in WT hearts both at baseline and after MI. In situ analysis revealed that cells near the ischemic border zone - likely cardiomyocytes -serve as the major sources of IL-10. In vitro studies using HL-1 murine cardiac cells confirmed that chemical hypoxia induces IL-10 expression, whereas preexisting DSBs blunt this response. Together, these findings suggest that DSB accumulation hinders cardiac repair after MI, potentially because of insufficient IL-10 expression in cardiomyocytes, thereby disturbing M2 macrophage recruitment. Targeting DNA damage pathways or enhancing IL-10 signaling in cardiomyocytes could represent a new therapeutic strategy to improve cardiac repair after MI.