Human single nuclear RNA sequencing identifies CD47 as a therapeutic target for doxorubicin-induced cardiomyopathy
Doxorubicin cardiomyopathy (DoxCM) remains a significant clinical problem, yet its underlying mechanisms remain incompletely understood. Identifying DoxCM mechanisms that can be translated into therapeutic interventions may improve patient outcomes. We performed single nuclear RNA-sequencing on left ventricular (LV) myocardial tissue from patients with DoxCM versus non-ischemic cardiomyopathy and non-failing donors. This approach aimed to elucidate 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.Compared to both donors and non-ischemic cardiomyopathy, 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. Our data support CD47 as a disease-specific target and promising therapeutic approach for mitigating cardiac dysfunction in DoxCM Overall design: We conducted single-nuclear RNA sequencing (snRNA-seq) on left ventricular myocardial tissues collected from donors who died without a history of heart failure (HF), and from those with end-stage HF due to either doxorubicin (Dox) or non-ischemic cardiomyopathy (NICM) without Dox exposure. *************************************************************** Submitter states that nine samples are missing raw files are due to file loss. ***************************************************************