Human Single-Nucleus RNA Sequencing Identifies CD47 as a Therapeutic Target for Doxorubicin-Induced Cardiomyopathy
Year: 2025
Type: article
Abstract: 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.
Source: Circulation
Authors: Zhen Guo, Anahita Ataran, Pan Ma, Wenjing Yu, Hamidreza Hajirezaei, Carla Valenzuela Ripoll, Lauren N. Pedersen, Omid Rashidi, Mandy M. Chan, Mengcheng Shen, Shannon Kelley, Alireza Sargazi, Mualla Ozcan, Aynaz Lotfinaghsh, Yoonje Cho, Ahmed Diab, Felicia Grogan, Amanda Klaas, Alexander Pompian, Adnan Imam, Rehman Lodhi, Amen Bekele Zelleke, Attila Kovacs, Kenneth B. Margulies, Jeff Szymanski, Marco Sardiello, Babak Razani, Aarti Asnani, Benjamin J. Kopecky, Pierre E. Signore, B. Alexander Yi, Craig T. Basson, Kodi S. Ravichandran, Sumanth D. Prabhu, Carmen Bergom, Joel D. Schilling, Kory J. Lavine, Ali Javaheri
Institutions: Washington University in St. Louis, Stanford Medicine, Stanford Cardiovascular Institute, Stanford University, Hospital of the University of Pennsylvania, University of Pennsylvania, University of Pittsburgh, Beth Israel Deaconess Medical Center, Harvard University, University of Colorado Anschutz, John Cochran VA Medical Center
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G106125584, G151374072, HIGH-RESOLUTON ULTRASOUND SYSTEM FOR PHENOTYPIC EVALUATION OF THE CARDIOVASCULAR SYSTEM IN MICE, PURCHASE OF AN IMAGE-GUIDED SMALL-ANIMAL IRRADIATOR, G2201063474, G2328495382, G2337220457, G3034295472, G3090873405, G444632500, G4604317009, G4961167568, G5464275290, G6279746626, Integrative genomics of human heart failure, Specification and Function of Tissue Resident and Recruited Macrophages in Cardiac Remodeling and Heart Failure
OpenAlex ID: W4413115709