Ecto-CD38-NADase inhibition modulates cardiac metabolism and protects mice against doxorubicin-induced cardiotoxicity
© 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.permissionsoup.com..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:120 |
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| Enthalten in: |
Cardiovascular research - 120(2024), 3 vom: 14. März, Seite 286-300 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Peclat, Thais R [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.03.2024 Date Revised 13.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/cvr/cvae025 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM367617021 |
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| 245 | 1 | 0 | |a Ecto-CD38-NADase inhibition modulates cardiac metabolism and protects mice against doxorubicin-induced cardiotoxicity |
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| 500 | |a Date Revised 13.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 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.permissionsoup.com. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CD38 | |
| 650 | 4 | |a Cardiotoxicity | |
| 650 | 4 | |a DIC | |
| 650 | 4 | |a Doxorubicin | |
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| 700 | 1 | |a Agorrody, Guillermo |e verfasserin |4 aut | |
| 700 | 1 | |a Colman, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Kashyap, Sonu |e verfasserin |4 aut | |
| 700 | 1 | |a Zeidler, Julianna D |e verfasserin |4 aut | |
| 700 | 1 | |a Chini, Claudia C S |e verfasserin |4 aut | |
| 700 | 1 | |a Warner, Gina M |e verfasserin |4 aut | |
| 700 | 1 | |a Thompson, Katie L |e verfasserin |4 aut | |
| 700 | 1 | |a Dalvi, Pranjali |e verfasserin |4 aut | |
| 700 | 1 | |a Beckedorff, Felipe |e verfasserin |4 aut | |
| 700 | 1 | |a Ebtehaj, Sanam |e verfasserin |4 aut | |
| 700 | 1 | |a Herrmann, Joerg |e verfasserin |4 aut | |
| 700 | 1 | |a van Schooten, Wim |e verfasserin |4 aut | |
| 700 | 1 | |a Chini, Eduardo Nunes |e verfasserin |4 aut | |
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