TARGETING ENDOTHELIAL-TO-MESENCHYMAL TRANSITION IN DOXORUBICIN-INDUCED CARDIOVASCULAR TOXICITY: THE ROLE OF CYP EPOXYGENASES AND SOLUBLE EPOXIDE HYDROLASE/CYCLOOXYGENASE-2 INHIBITION

Abstract

Background: Doxorubicin (DOX) is an anthracycline widely used against many neoplastic diseases. However, the clinical use of DOX is limited due to its dose-dependent cardiovascular toxicity. Recent studies suggest that Endothelial-to-Mesenchymal transition (EndMT) and endothelial toxicity may contribute to the pathogenesis of DOX-induced cardiovascular toxicity. Given that Arachidonic Acid (AA) and associated Cytochrome P450 (CYP) epoxygenase, soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) have been involved in vascular endothelial and cardiovascular function, we aimed to examine the effect of suppressing CYP epoxygenases using MSPPOH on DOX-induced EndMT and cardiotoxicity. We also aimed to investigate the effect of PTUPB, a dual sEH/COX-2 inhibitor, on DOX-induced EndMT, vascular and cardiac toxicity. Methods: Human endothelial cells were treated with DOX, with/without CYP epoxygenase inhibitor, MSPPOH. We also investigated the effect of MSPPOH on the cardiovascular system in zebrafish. Additionally, we tested the potential beneficial impact of PTUPB on DOX-induced cardiovascular toxicity in zebrafish and DOX-induced EndMT in human endothelial cells. Results: Inhibiting CYP epoxygenase using MSPPOH exacerbated DOX-induced EndMT, inflammation, oxidative stress and apoptosis in our endothelial cells. Furthermore, MSPPOH increased cardiac edema, lowered blood flow velocity, and worsened the expression of EndMT and cardiac injury markers in a zebrafish model of DOX-induced cardiovascular toxicity. Conversely, inhibition of sEH and COX-2 using PTUPB reduces DOX-induced EndMT and vascular toxicity. Also, PTUPB improves cardiac function and morphology in zebrafish incubated with DOX. Importantly, our results demonstrate that PTUPB downregulates inflammation and oxidative stress markers to contribute to the improvement observed in DOX-induced cardiovascular toxicity. Conclusion: Our data indicates that a selective CYP epoxygenase inhibitor, MSPPOH, worsens DOX-induced EndMT vascular and cardiac toxicity. On the other hand, suppressing sEH/COX-2 using PTUPB reduces DOX-induced EndMT, vascular, and cardiac toxicity.