DNA-damaging Chemotherapy altered the Cardiac Pathogenesis by reshaping the Composition and Functionality of Cardiac Resident Macrophages (bulk RNA-Seq).

Cardiovascular comorbidities including heart failure and ischemic heart injury represent the most common causes of death among cancer survivors. Despite extensive investigation, we continue to have a poor understanding of how previous chemotherapy reagents exposure impact the heart. Here, we investigated the effect of chemotherapy reagent on the composition and function of the cardiac resident macrophages and found carboplatin selectively deplete the CCR2¬¬¬¬– cardiac macrophages by activating P53 signaling pathway and inducing necroptosis and apoptosis. Using Bulk-RNA-seq and lineage-tracing mice, we found CCR2– cardiac macrophages returned after Carboplatin-exposure primarily from monocytes recruitment and demonstrated a different transcriptomic profile. These reshaped CRMs attenuated heart remodeling upon hypertensive heart injury and ischemic-reperfusion injury while selective ablation of the reshaped CRMs abolished this mitigation phenotype. Using bulk-seq, single-cell RNA seq and lineage-tracing mice, we showed that the reshaped CRMs in carboplatin-exposed mice mitigated ventricle remodeling via elevated IFN-I signaling. Together, this study characterized how DNA-damaging chemotherapy reagent change the cardiac immune landscape and demonstrated a novel protective mechanism in adverse cardiac injury response that depends on the carboplatin-reshaped CRMs. These findings highlight the importance of type-I interferon signaling in the long-term effect of chemotherapy and provide promising pathway to retard cardiac pathogenesis.