학술논문
Ecto-CD38-NADase inhibition modulates cardiac metabolism and protects mice against doxorubicin-induced cardiotoxicity.
Document Type
Academic Journal
Author
Peclat TR; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.; Agorrody G; Departamento de Fisiopatologia, Hospital de Clínicas, Facultad de Medicina, Universidad de la Republica, Montevideo, Uruguay.; Laboratorio de Patologías del Metabolismo y el Envejecimiento, Institut Pasteur de Montevideo, Montevideo, Uruguay.; Colman L; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.; Kashyap S; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.; Zeidler JD; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.; Chini CCS; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.; Warner GM; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.; Thompson KL; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.; Dalvi P; Ancora Biotech, Inc.; Beckedorff F; Sylvester Comprehensive Cancer Center, Department of Human Genetics, Biomedical Research Building, University of Miami Miller School of Medicine, Miami, FL 33136, USA.; Ebtehaj S; Division of Ischemic Heart Disease and Critical Care, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55902, USA.; Herrmann J; Division of Ischemic Heart Disease and Critical Care, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55902, USA.; van Schooten W; Ancora Biotech, Inc.; Chini EN; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.; Departamento de Fisiopatologia, Hospital de Clínicas, Facultad de Medicina, Universidad de la Republica, Montevideo, Uruguay.; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
Source
Publisher: Oxford Journals Country of Publication: England NLM ID: 0077427 Publication Model: Print Cited Medium: Internet ISSN: 1755-3245 (Electronic) Linking ISSN: 00086363 NLM ISO Abbreviation: Cardiovasc Res Subsets: MEDLINE
Subject
Language
English
Abstract
Aims: Doxorubicin (DXR) is a chemotherapeutic agent that causes dose-dependent cardiotoxicity. Recently, it has been proposed that the NADase CD38 may play a role in doxorubicin-induced cardiotoxicity (DIC). CD38 is the main NAD+-catabolizing enzyme in mammalian tissues. Interestingly, in the heart, CD38 is mostly expressed as an ecto-enzyme that can be targeted by specific inhibitory antibodies. The goal of the present study is to characterize the role of CD38 ecto-enzymatic activity in cardiac metabolism and the development of DIC.
Methods and Results: Using both a transgenic animal model and a non-cytotoxic enzymatic anti-CD38 antibody, we investigated the role of CD38 and its ecto-NADase activity in DIC in pre-clinical models. First, we observed that DIC was prevented in the CD38 catalytically inactive (CD38-CI) transgenic mice. Both left ventricular systolic function and exercise capacity were decreased in wild-type but not in CD38-CI mice treated with DXR. Second, blocking CD38-NADase activity with the specific antibody 68 (Ab68) likewise protected mice against DIC and decreased DXR-related mortality by 50%. A reduction of DXR-induced mitochondrial dysfunction, energy deficiency, and inflammation gene expression were identified as the main mechanisms mediating the protective effects.
Conclusion: NAD+-preserving strategies by inactivation of CD38 via a genetic or a pharmacological-based approach improve cardiac energetics and reduce cardiac inflammation and dysfunction otherwise seen in an acute DXR cardiotoxicity model.
Competing Interests: Conflict of interest: E.N.C. holds a patent on the use of CD38 inhibitors for metabolic diseases licensed by Elysium Health. E.N.C. is a consultant for TeneoBio, Calico, Mitobridge, and Cytokinetics. E.N.C. is on the advisory board of Eolo Pharma. E.N.C. and WVS own stocks in TeneoBio. Research in the E.N.C. laboratory has been conducted in compliance with Mayo Clinic’s conflict of interest policies.
(© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Methods and Results: Using both a transgenic animal model and a non-cytotoxic enzymatic anti-CD38 antibody, we investigated the role of CD38 and its ecto-NADase activity in DIC in pre-clinical models. First, we observed that DIC was prevented in the CD38 catalytically inactive (CD38-CI) transgenic mice. Both left ventricular systolic function and exercise capacity were decreased in wild-type but not in CD38-CI mice treated with DXR. Second, blocking CD38-NADase activity with the specific antibody 68 (Ab68) likewise protected mice against DIC and decreased DXR-related mortality by 50%. A reduction of DXR-induced mitochondrial dysfunction, energy deficiency, and inflammation gene expression were identified as the main mechanisms mediating the protective effects.
Conclusion: NAD+-preserving strategies by inactivation of CD38 via a genetic or a pharmacological-based approach improve cardiac energetics and reduce cardiac inflammation and dysfunction otherwise seen in an acute DXR cardiotoxicity model.
Competing Interests: Conflict of interest: E.N.C. holds a patent on the use of CD38 inhibitors for metabolic diseases licensed by Elysium Health. E.N.C. is a consultant for TeneoBio, Calico, Mitobridge, and Cytokinetics. E.N.C. is on the advisory board of Eolo Pharma. E.N.C. and WVS own stocks in TeneoBio. Research in the E.N.C. laboratory has been conducted in compliance with Mayo Clinic’s conflict of interest policies.
(© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)