Abstract 4359291: Human single-nucleus RNA sequencing identifies CD47 as a therapeutic target for doxorubicin-induced cardiomyopathy

Abstract

Background: Doxorubicin cardiomyopathy (DoxCM) remains a significant clinical problem, yet its underlying mechanisms remain incompletely understood. Identifying DoxCM mechanisms can lead to therapeutic interventions that improve patient outcomes. Methods: We performed single nucleus RNA-sequencing on left ventricular (LV) myocardial tissue from patients with DoxCM versus non-ischemic cardiomyopathy and non-failing donors. This approach aimed to uncover the transcriptional changes associated with DoxCM. Additionally, we conducted immunostaining, flow cytometry, antibody neutralization, and cell depletion studies to validate our findings and define in vivo mechanisms. Results: Compared to non-failing donors and non-ischemic cardiomyopathy patients, LV myocardium from DoxCM patients exhibited increased periostin-positive (POSTN + ) activated fibroblasts, down-regulation of genes involved in phagocytosis, and increased expression of the anti-phagocytic molecule CD47. Immunostaining of human cardiac sections and murine studies demonstrated increased POSTN + cells and CD47 in DoxCM and in a murine breast cancer model. CD47 antibody neutralization both prevented and treated Dox-induced reduction in LV ejection fraction and fibrosis. Mechanistically, depletion of resident cardiac macrophages blocked the cardioprotective effects of CD47 neutralization and clearance of cardiac fibroblasts. Conclusions: Our data support CD47 as a disease-specific target and promising therapeutic approach for mitigating cardiac dysfunction in DoxCM.