Inhibition of cytochrome P450 epoxygenase promotes endothelium-to-mesenchymal transition and exacerbates doxorubicin-induced cardiovascular toxicity

• Published in: Molecular biology reports 2024-12, Vol.51 (1), p.859, Article 859
• Main Authors: Dhulkifle, Hevna, Therachiyil, Lubna, Hasan, Maram H., Sayed, Tahseen S., Younis, Shahd M., Korashy, Hesham M., Yalcin, Huseyin C., Maayah, Zaid H.
• Format: Article
• Language: English
• Subjects: Animal Anatomy; Animal Biochemistry; Animals; Apoptosis; Apoptosis - drug effects; Arachidonic acid; Biomedical and Life Sciences; Blood flow; Cardiotoxicity; Cardiotoxicity - etiology; Cardiotoxicity - metabolism; Cardiovascular diseases; Cardiovascular system; Chemotherapy; Cytochrome; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Danio rerio; Doxorubicin; Doxorubicin - adverse effects; Edema; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium; Epithelial-Mesenchymal Transition - drug effects; Flow velocity; Heart; Histology; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Life Sciences; Molecular modelling; Morphology; Original; Original Article; Oxidative stress; Oxidative Stress - drug effects; Quality of life; Toxicity; Zebrafish
• ISSN: 0301-4851; 1573-4978; 1573-4978
• DOI: 10.1007/s11033-024-09803-z

Background Doxorubicin (DOX) is a potent chemotherapy widely used in treating various neoplastic diseases. However, the clinical use of DOX is limited due to its potential toxic effect on the cardiovascular system. Thus, identifying the pathway involved in this toxicity may help minimize chemotherapy risk and improve cancer patients’ quality of life. Recent studies suggest that Endothelial-to-Mesenchymal transition (EndMT) and endothelial toxicity contribute to the pathogenesis of DOX-induced cardiovascular toxicity. However, the molecular mechanism is yet unknown. Given that arachidonic acid and associated cytochrome P450 (CYP) epoxygenase have been involved in endothelial and cardiovascular function, we aimed to examine the effect of suppressing CYP epoxygenases on DOX-induced EndMT and cardiovascular toxicity in vitro and in vivo. Methods and Results To test this, human endothelial cells were treated with DOX, with or without CYP epoxygenase inhibitor, MSPPOH. We also investigated the effect of MSPPOH on the cardiovascular system in our zebrafish model of DOX-induced cardiotoxicity. Our results showed that MSPPOH exacerbated DOX-induced EndMT, inflammation, oxidative stress, and apoptosis in our endothelial cells. Furthermore, we also show that MSPPOH increased cardiac edema, lowered vascular blood flow velocity, and worsened the expression of EndMT and cardiac injury markers in our zebrafish model of DOX-induced cardiotoxicity. Conclusion Our data indicate that a selective CYP epoxygenase inhibitor, MSPPOH, induces EndMT and endothelial toxicity to contribute to DOX-induced cardiovascular toxicity.