{"doi":"10.1101/2021.01.12.426397","title":"Apolipoprotein M attenuates anthracycline cardiotoxicity and lysosomal injury","abstract":"Abstract Objectives Determine the role of apolipoprotein M (ApoM) in anthracycline (Dox) cardiotoxicity. Background ApoM binds the cardioprotective sphingolipid sphingosine-1-phosphate (S1P). Circulating ApoM is inversely associated with mortality in human heart failure (HF). Methods In the Penn HF Study (PHFS), we tested the relationship between ApoM and mortality in a subset with anthracycline-induced cardiomyopathy. We measured ApoM in humans and mice treated with Dox and utilized hepatic ApoM transgenic ( Apom TG ), ApoM knockout ( Apom KO ), ApoM knock-in mice with impaired S1P binding, and S1P receptor 3 (S1PR3) knockout mice in Dox cardiotoxicity. We assayed autophagy in left ventricular tissue from anthracycline-induced HF patients versus donor controls. Results ApoM was inversely associated with mortality in PHFS, and Dox reduced circulating ApoM in mice and breast cancer patients. Apom TG mice were protected from Dox-induced cardiac dysfunction and loss of left ventricular mass. Apom TG attenuated Dox-induced impairment in autophagic flux in vivo and accumulation of insoluble p62, which was also observed in the myocardium of patients with anthracycline-induced HF. In vehicle-treated mice, ApoM negatively regulated transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. The effect of ApoM on TFEB required both S1P binding and S1PR3. In the presence of Dox, ApoM preserved TFEB and cardiomyocyte lysosomal abundance assessed as lysosomal associated membrane protein 1 positive structures in vivo, while S1P mimetic pretreatment of cardiomyocytes prevented Dox-induced changes in lysosomal pH. Conclusions ApoM attenuates Dox cardiotoxicity via the autophagy-lysosome pathway. The association between ApoM and reduced mortality may be explained by its role in sustaining autophagy. Highlights Circulating ApoM is inversely associated with survival in human anthracycline-induced cardiomyopathy Anthracycline treatment reduces circulating ApoM in humans and mice Increasing ApoM attenuates doxorubicin cardiotoxicity, lysosomal injury and preserves myocardial autophagic flux, but does not impact doxorubicin anti-neoplastic efficacy Autophagic impairment is characteristic of human anthracycline cardiomyopathy","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":216309,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":812221,"name":"Carla Valenzuela Ripoll","orcid":"0000-0002-6177-5227","position":1,"is_corresponding":false},{"id":812746,"name":"Antonino Picataggi","orcid":null,"position":2,"is_corresponding":false},{"id":413233,"name":"David R. Rawnsley","orcid":"0000-0002-1620-8637","position":3,"is_corresponding":false},{"id":812222,"name":"Mualla Özcan","orcid":"0000-0002-1763-5454","position":4,"is_corresponding":false},{"id":228821,"name":"Julio A. Chirinos","orcid":"0000-0001-9035-5670","position":5,"is_corresponding":false},{"id":812223,"name":"Ezhilarasi Chendamarai","orcid":"0000-0001-7032-9301","position":6,"is_corresponding":false},{"id":812224,"name":"Amanda Girardi","orcid":"0000-0002-1263-1462","position":7,"is_corresponding":false},{"id":812747,"name":"Terrence E. Riehl","orcid":null,"position":8,"is_corresponding":false},{"id":812748,"name":"Hosannah Evie","orcid":null,"position":9,"is_corresponding":false},{"id":812225,"name":"Ahmed Diab","orcid":"0000-0002-1891-3620","position":10,"is_corresponding":false},{"id":753236,"name":"Tibor Kovács","orcid":"0000-0002-0632-9128","position":11,"is_corresponding":false},{"id":699179,"name":"Krzysztof Hyrc","orcid":"0000-0002-8830-6324","position":12,"is_corresponding":false},{"id":239379,"name":"Xiucui Ma","orcid":null,"position":13,"is_corresponding":false},{"id":268420,"name":"Aarti Asnani","orcid":"0000-0003-4967-9918","position":14,"is_corresponding":false},{"id":260475,"name":"Swapnil V. Shewale","orcid":"0000-0001-8373-9692","position":15,"is_corresponding":false},{"id":255209,"name":"Marielle Scherrer‐Crosbie","orcid":"0000-0001-6375-9266","position":16,"is_corresponding":false},{"id":339452,"name":"L. Ashley Cowart","orcid":"0000-0002-5312-5232","position":17,"is_corresponding":false},{"id":299668,"name":"John S. Parks","orcid":"0000-0002-5227-8915","position":18,"is_corresponding":false},{"id":228814,"name":"Lei Zhao","orcid":"0000-0001-5027-2379","position":19,"is_corresponding":false},{"id":812226,"name":"David Gordon","orcid":"0000-0003-2188-7766","position":20,"is_corresponding":false},{"id":350496,"name":"Francisco Ramírez‐Valle","orcid":"0000-0002-8625-5869","position":21,"is_corresponding":false},{"id":30817,"name":"Kenneth B. Margulies","orcid":"0000-0002-8093-4465","position":22,"is_corresponding":false},{"id":30818,"name":"Thomas P. Cappola","orcid":"0000-0002-9630-7204","position":23,"is_corresponding":false},{"id":304419,"name":"Ankit A. Desai","orcid":"0000-0001-6427-616X","position":24,"is_corresponding":false},{"id":812749,"name":"Lauren N. Pederson","orcid":null,"position":25,"is_corresponding":false},{"id":296246,"name":"Carmen Bergom","orcid":"0000-0002-0886-5055","position":26,"is_corresponding":false},{"id":231458,"name":"Nathan O. Stitziel","orcid":"0000-0002-4963-8211","position":27,"is_corresponding":false},{"id":233372,"name":"Michael P. Rettig","orcid":"0000-0002-1091-0564","position":28,"is_corresponding":false},{"id":18437,"name":"John F. Dipersio","orcid":"0000-0002-0429-3133","position":29,"is_corresponding":false},{"id":812227,"name":"Stefan Hajny","orcid":"0000-0002-4178-7968","position":30,"is_corresponding":false},{"id":350977,"name":"Christina Christoffersen","orcid":"0000-0003-3751-5203","position":31,"is_corresponding":false},{"id":238348,"name":"Abhinav Diwan","orcid":"0000-0001-7554-4772","position":32,"is_corresponding":false},{"id":263663,"name":"Ali Javaheri","orcid":"0000-0001-6657-331X","position":33,"is_corresponding":false},{"id":812220,"name":"Zhen Guo","orcid":"0000-0002-8421-4852","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:11.245932Z","pmid":null,"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":[]}