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, 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.
Article Details
Authors (38)
Zhen Guo
CAS Key Lab of Bio-Medical Diagnostics
Anahita Ataran
Washington university in St. Louis, Saint Louis, Missouri, United States
Pan Ma
Wenjing Yu
Hamidreza Hajirezaei
Department 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.
Carla Valenzuela Ripoll
Lauren N. Pedersen
Department 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.
Omid Rashidi
Department 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.
Mandy M. Chan
Department 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.
Mengcheng Shen
Department 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.
Shannon Kelley
Department of Pathology & Immunology, Division of Biology & Biomedical Sciences (S.K., K.S.R.), Washington University School of Medicine, St Louis, MO.
Alireza Sargazi
Department 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.
Mualla Ozcan
Aynaz Lotfinaghsh
Department 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.
Yoonje Cho
Department 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.
Ahmed Diab
Department 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.
Felicia Grogan
Department of Radiation Oncology (F.G., A. Klaas, J.S., C.B.), Washington University School of Medicine, St Louis, MO.
Amanda Klaas
Department of Radiation Oncology (F.G., A. Klaas, J.S., C.B.), Washington University School of Medicine, St Louis, MO.
Alexander Pompian
Department 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.
Adnan Imam
Department 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.
Rehman Lodhi
Department 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.
Amen Bekele Zelleke
Department 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.
Attila Kovács
European Commission, Joint Research Centre, Postfach 2340, 76125 Karlsruhe, Germany
Kenneth B. Margulies
Cardiovascular Institute, Perelman School of Medicine, Division of Cardiology, University of Pennsylvania
Jeff Szymanski
Department of Radiation Oncology (F.G., A. Klaas, J.S., C.B.), Washington University School of Medicine, St Louis, MO.
Marco Sardiello
Babak Razani
Aarti Asnani
Beth Israel Deaconess, Arlington, Massachusetts, United States
Benjamin J. Kopecky
University of Colorado Anschutz Medical Center, Division of Cardiology, Aurora, CO (A.V.A., B.J.K.).
Pierre E. Signore
Bitterroot Bio, Palo Alto, CA (P.E.S., B.A.Y., C.T.B.).
B. Alexander Yi
Bitterroot Bio, Palo Alto, California, United States
Craig T. Basson
Department of Radiation Oncology (F.G., A. Klaas, J.S., C.B.), Washington University School of Medicine, St Louis, MO.
Kodi S. Ravichandran
Sumanth D. Prabhu
Department 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.
Carmen Bergom
Washington University in St. Louis, Saint Louis, Missouri, United States
Joel D. Schilling
Department 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.
Kory J. Lavine
Ali Javaheri