Letter by Shi et al Regarding Article, “Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy”

HomeCirculationVol. 147, No. 13Letter by Shi et al Regarding Article, “Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Shi et al Regarding Article, “Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy” Rui Shi, Feng Fu and Mingge Ding Rui ShiRui Shi Department of Geriatrics Cardiology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China (R.S., M.D.). Search for more papers by this author , Feng FuFeng Fu https://orcid.org/0000-0003-3752-4628 Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, Shaanxi, China (F.F.). Search for more papers by this author and Mingge DingMingge Ding https://orcid.org/0000-0001-9121-5151 Department of Geriatrics Cardiology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China (R.S., M.D.). Search for more papers by this author Originally published27 Mar 2023https://doi.org/10.1161/CIRCULATIONAHA.122.063010Circulation. 2023;147:1050To the Editor:We read with interest the article by Dhingra et al1 who demonstrated that the cardiotoxic properties of doxorubicin (Dox) are mediated by proteasomal degradation of the innate immune adapter protein TRAF2 (tumor necrosis factor receptor associated factor 2). This study provides an interesting observation that restoration of TRAF2 in vitro and in vivo suppressed Dox-induced mitochondrial injury and necrotic cell death and rescued cardiac function.We are interested in knowing whether TRAF2 administration affects the antitumor activity of Dox. Ideal cardioprotective therapies should not only reduce the cardiotoxicity of Dox but also retain or even augment Dox’s anticancer activity. One recent study highlighted that TRAF2 is an oncogenic regulator of Wnt/β-catenin signaling and colon cancer.2 Another study has shown that TRAF2 in osteotropic breast cancer cells enhances skeletal tumor growth and promotes osteolysis.3 Thus, assessing the effect of TRAF2 on Dox’s anticancer efficacy in Dox-sensitive tumor models may be important, because it directly relates to whether TRAF2 could be an effective therapeutic target for Dox-induced cardiotoxicity.Moreover, we are concerned that the concentration of Dox in vitro (10 μmol/L) may not match the dose of Dox in vivo (5 mg/kg intraperitoneally per week for 4 weeks) in this study. The pharmacokinetic analysis has shown that the median plasma concentration of Dox is around 1 μg/mL (equivalent to 1.8 μmol/L) and the area under the plasma drug concentration-time curve (AUC, a reflection of the actual body exposure to drug) is about 26.87 h·µg/mL (equivalent to 49.5 h·μmol/L) after the intraperitoneal administration of Dox at a 6 mg/kg dose.4 Previous studies mostly used a cellular model of 1 to 2 μmol/L Dox for 24 hours.5 Under in vitro conditions, drug concentration is considered constant. It is estimated that AUC approximately reaches 24 to 48 h·μmol/L. This exposure condition in vitro is able to reproduce the median plasma concentration or AUC of the Dox in vivo. In the present study, the cardiomyocytes were treated with 10 μmol/L Dox for 18 hours (AUC reaches approximately 180 h·μmol/L). Both the concentration and AUC of Dox in vitro are likely much higher than those in vivo. Therefore, it is desirable to discuss the regulatory role and mechanism of TRAF2 under the more suitable concentration of Dox in vitro.Article InformationSources of FundingThis work was supported by a grant from National Natural Science Foundation of China (No. 81970316).Disclosures None.FootnotesCirculation is available at www.ahajournals.org/journal/circReferences1. Dhingra R, Rabinovich-Nikitin I, Rothman S, Guberman M, Gang H, Margulets V, Jassal DS, Alagarsamy KN, Dhingra S, Valenzuela Ripoll C, et al. Proteasomal degradation of TRAF2 mediates mitochondrial dysfunction in doxorubicin-cardiomyopathy.Circulation. 2022; 146:934–954. doi: 10.1161/CIRCULATIONAHA.121.058411LinkGoogle Scholar2. Yan R, Zhu H, Huang P, Yang M, Shen M, Pan Y, Zhang C, Zhou X, Li H, Ke X, et al. Liquidambaric acid inhibits Wnt/beta-catenin signaling and colon cancer via targeting TNF receptor-associated factor 2.Cell Rep. 2022; 38:110319. doi: 10.1016/j.celrep.2022.110319CrossrefMedlineGoogle Scholar3. Peramuhendige P, Marino S, Bishop RT, de Ridder D, Khogeer A, Baldini I, Capulli M, Rucci N, Idris AI. TRAF2 in osteotropic breast cancer cells enhances skeletal tumour growth and promotes osteolysis.Sci Rep. 2018; 8:39. doi: 10.1038/s41598-017-18327-5CrossrefMedlineGoogle Scholar4. Durna Corum D, Uney K. Gender differences in the effect of calcitriol on the body disposition and excretion of doxorubicin in mice.Eur J Drug Metab Pharmacokinet. 2020; 45:653–664. doi: 10.1007/s13318-020-00632-6CrossrefMedlineGoogle Scholar5. Prathumsap N, Shinlapawittayatorn K, Chattipakorn SC, Chattipakorn N. Effects of doxorubicin on the heart: From molecular mechanisms to intervention strategies.Eur J Pharmacol. 2020; 866:172818. doi: 10.1016/j.ejphar.2019.172818CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails March 28, 2023Vol 147, Issue 13 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.063010PMID: 36972345 Originally publishedMarch 27, 2023 PDF download Advertisement SubjectsCardiotoxicityNeuroprotectantsThrombosis