Related Experiment Video
Updated: May 8, 2026
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Human Single-Nucleus RNA Sequencing Identifies CD47 as a Therapeutic Target for Doxorubicin-Induced Cardiomyopathy
Zhen Guo1, Anahita Ataran1, Pan Ma1
1Department of Medicine, Division of Cardiology (Z.G., A.Ataran, P.M., Y.W., H.H., C.V.R., L.N.P., O.R., M.M.C., M.Shen, A.S., M.O., A.L., Y.C., A.D., A.P., A.I., R.L., A.B.Z., A.Kovacs, S.D.P., J.D.S., K.J.L., A.J.), Washington University School of Medicine, St Louis, MO.
Background:
Doxorubicin cardiomyopathy (DoxCM) remains a significant clinical problem, but 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 myocardial tissue from patients with DoxCM versus nonischemic cardiomyopathy and nonfailing 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 with nonfailing donors and patients with nonischemic cardiomyopathy, left ventricular myocardium from patients with DoxCM exhibited increased POSTN (periostin)+ activated fibroblasts, downregulation of genes involved in phagocytosis, and increased expression of the antiphagocytic 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 doxorubicin-induced reduction in left ventricular 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.
Insights
Doxorubicin-induced cardiomyopathy (DoxCM) involves increased CD47 expression, hindering cardiac repair. Neutralizing CD47 protected heart function and reduced fibrosis, offering a new therapeutic strategy for DoxCM.
Area of Science:
- Cardiology
- Oncology
- Immunology
Background:
- Doxorubicin cardiomyopathy (DoxCM) is a major clinical challenge with poorly understood mechanisms.
- Identifying DoxCM mechanisms is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the molecular mechanisms underlying DoxCM.
- To identify potential therapeutic targets for DoxCM.
Main Methods:
- Single-nucleus RNA sequencing of left ventricular myocardial tissue from DoxCM patients, nonischemic cardiomyopathy patients, and healthy donors.
- Immunostaining, flow cytometry, antibody neutralization, and cell depletion studies in human and murine models.
- Validation of transcriptional changes and in vivo mechanistic studies.
Main Results:
- DoxCM hearts showed increased periostin (POSTN)+ activated fibroblasts, reduced phagocytic gene expression, and elevated CD47.
- Increased POSTN+ cells and CD47 were observed in human DoxCM and a murine breast cancer model.
- CD47 antibody neutralization prevented and treated doxorubicin-induced cardiac dysfunction and fibrosis.
- Depletion of cardiac macrophages abolished the cardioprotective effects of CD47 neutralization.
Conclusions:
- CD47 is a disease-specific target for DoxCM.
- CD47 antibody neutralization represents a promising therapeutic strategy for mitigating cardiac dysfunction in DoxCM.
Related Concept Videos
01:23RNA Interference
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase