CYP2J2-derived epoxyeicosatrienoic acids protect against doxorubicin-induced cardiotoxicity by reducing oxidative stress and apoptosis via activation of the AMPK pathway

Zhu, Chuanmeng; Bai, Yang; Qiu, Jie; Chen, Guangzhi; Guo, Xiaomei; Xu, Renfan

doi:10.1016/j.heliyon.2023.e23526

Heliyon

2024

DOI: 10.1016/j.heliyon.2023.e23526

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CYP2J2-derived epoxyeicosatrienoic acids protect against doxorubicin-induced cardiotoxicity by reducing oxidative stress and apoptosis via activation of the AMPK pathway

Chuanmeng Zhu,

Yang Bai,

Jie Qiu

et al.

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2024

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

Dhulkifle,

Therachiyil,

Hasan

et al. 2024

Mol Biol Rep

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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.

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

Dhulkifle,

Therachiyil,

Hasan

et al. 2024

Mol Biol Rep

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CYP2J2-derived epoxyeicosatrienoic acids protect against doxorubicin-induced cardiotoxicity by reducing oxidative stress and apoptosis via activation of the AMPK pathway

Cited by 1 publication

References 36 publications

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

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

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