At the heart of toxicity : connexin-43 alterations in doxorubicin-induced cardiac dysfunction

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Veerman, Ben and Wahid, Maheen and MacKenzie, Graeme and Tinto, Kirsty and Wu, Jia and Hamilton, Benjamin and Rattray, Zahra and Macquaide, Niall and Currie, Susan and Cunningham, Margaret Rose (2026) At the heart of toxicity : connexin-43 alterations in doxorubicin-induced cardiac dysfunction. In: The Scottish Cardiovascular Forum, 2026-03-21 - 2026-03-21, The James McCune Smith Building (Room 745) - University of Glasgow.

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Abstract

Introduction: Doxorubicin (DOX) is an effective anthracycline chemotherapeutic agent whose clinical utility is limited by cumulative cardiotoxicity, manifesting as arrhythmias, contractile dysfunction, and dilated cardiomyopathy [1]. Connexin-43 (Cx43), the predominant cardiac gap-junctional important role in intercellular communication and cardiac function. Dysregulation of Cx43 has been implicated in cardiac dysfunction [2,3], yet its role in DOX-induced cardiotoxicity remains incompletely understood. Aims: To investigate how DOX alters Cx43 expression and localisation in cardiac and vascular cells, ex vivo rat hearts, and 3D human cardiac spheroid models, and to determine how these changes relate to ventricular contractility. Cx43-related effects were also examined in cancer cells to assess context specificity. Methods: Human coronary artery endothelial cells, AC16 cardiomyocytes and cardiac fibroblasts were treated with DOX. Cx43 expression and localisation were analysed using Western blotting and immunofluorescence. Langendorff-perfused rat hearts, organ bath-stimulated ventricular preparations, and human 3D contractile tri-cell cardiac spheroids were used to assess multi-cellular and tissue-level responses. Parallel experiments were conducted in MDA-MB-231 breast cancer cells. Results: DOX reduced Cx43 protein levels in multiple human cardiac and vascular cell types. In contrast, Langendorff-perfused hearts demonstrated increased ventricular Cx43 expression with lateralisation in cardiomyocytes. Acute alterations in left ventricular Cx43 expression were similarly observed in organ bath preparations. In 3D human cardiac spheroids, overall Cx43 expression was preserved; however, DOX significantly impaired contractility and calcium handling. No significant Cx43 alterations were detected in cancer cells. This suggests that these effects were limited to the cardiac niche. Discussion: DOX induces context-dependent Cx43 alterations, characterised by differential expression and redistribution across experimental models. These alterations, along with impaired calcium handling, may contribute to electrical and contractile dysfunction. This highlights Cx43 as a potential biomarker and therapeutic target in cardio-oncology. References: 1. Sheibani M, Azizi Y, Shayan M, Nezamoleslami S, Eslami F, Farjoo MH, Dehpour AR. Doxorubicin-Induced Cardiotoxicity: An Overview on Pre-clinical Therapeutic Approaches. Cardiovascular Toxicology. 2022;22(4):292-310. https://dx.doi.org/10.1007/s12012-022-09721-1 2. Pun R, Kim MH, North BJ. Role of Connexin 43 phosphorylation on Serine-368 by PKC in cardiac function and disease. Frontiers in Cardiovascular Medicine. 2023;9. https://dx.doi.org/10.3389/fcvm.2022.1080131 3. Araujo PA, Muñoz M, Quan J, Contreras JE. Connexin‐43 remodelling and arrhythmias: hemichannels as key drivers of cardiac dysfunction. The Journal of Physiology. 2025;603(15):4293-306. https://dx.doi.org/10.1113/jp288091

ORCID iDs

Veerman, Ben, Wahid, Maheen ORCID logoORCID: https://orcid.org/0000-0003-1500-0671, MacKenzie, Graeme, Tinto, Kirsty ORCID logoORCID: https://orcid.org/0009-0008-7954-0742, Wu, Jia, Hamilton, Benjamin, Rattray, Zahra ORCID logoORCID: https://orcid.org/0000-0002-8371-8549, Macquaide, Niall, Currie, Susan ORCID logoORCID: https://orcid.org/0000-0002-4237-4428 and Cunningham, Margaret Rose ORCID logoORCID: https://orcid.org/0000-0001-6454-8671;
  • Item type:Conference or Workshop Item(Poster)
    ID code:95910
    Dates:
    Date
    Event
    21 March 2026
    Published
    Notes:The poster was presented by Jia Wu, a fourth year Pharmacology and Biochemistry Undergraduate student at the Strathclyde Institute of Pharmacy and Biomedical Sciences
    Subjects:Medicine > Internal medicine
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:30 Mar 2026 15:01
    Last modified:06 Jun 2026 00:04
    URI:https://strathprints.strath.ac.uk/id/eprint/95910
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