{"doi":"10.1093/cvr/cvae025","title":"Ecto-CD38-NADase inhibition modulates cardiac metabolism and protects mice against doxorubicin-induced cardiotoxicity","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.","journal":"Cardiovascular Research","year":2024,"id":453256,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9622,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1176378,"name":"Guillermo Agorrody","orcid":"0000-0002-9241-6681","position":1,"is_corresponding":false},{"id":1275784,"name":"Laura Colman","orcid":"0009-0006-6749-8810","position":2,"is_corresponding":false},{"id":619211,"name":"Sonu Kashyap","orcid":"0000-0002-9992-251X","position":3,"is_corresponding":false},{"id":619210,"name":"Julianna D. Zeidler","orcid":"0000-0003-3168-1518","position":4,"is_corresponding":false},{"id":902950,"name":"Claudia C.S. Chini","orcid":"0000-0002-7499-8921","position":5,"is_corresponding":false},{"id":639580,"name":"Gina M. Warner","orcid":null,"position":6,"is_corresponding":false},{"id":865284,"name":"Katie L. Thompson","orcid":null,"position":7,"is_corresponding":false},{"id":574742,"name":"Pranjali Dalvi","orcid":"0000-0002-5247-9645","position":8,"is_corresponding":false},{"id":265865,"name":"Felipe Beckedorff","orcid":"0000-0001-6735-6851","position":9,"is_corresponding":false},{"id":1275785,"name":"Sanam Ebtehaj","orcid":"0000-0003-2487-8013","position":10,"is_corresponding":false},{"id":488011,"name":"Joerg Herrmann","orcid":"0000-0001-6675-4559","position":11,"is_corresponding":false},{"id":649047,"name":"Wim van Schooten","orcid":null,"position":12,"is_corresponding":false},{"id":256584,"name":"Eduardo N. Chini","orcid":"0000-0003-1555-4834","position":13,"is_corresponding":false},{"id":586754,"name":"Thais Peclat","orcid":"0000-0002-8907-5548","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-19T02:02:58.784290Z","pmid":"38271281","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}