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

الموضوعات

طب

الملخص

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.

روابط وملفات

التعريف والنوع

رقم الوثيقة

0547563f-ed0c-4221-9ed3-47c391cbc1f1

رقم العقد

0

نوع الوسائط

Crawler

نوع المحتوى

الرسائل العلمية

صيغة المصدر

رسائل ماجيستير

نوع الملف

pdf text

أسماء الملفات

797893_1.pdf

بيانات النشر

ألقاب المؤلفين

[{"name_ar":"Hevna Dhulkifle","title_ar":"اعداد","title_en":"Preparation"},{"name_ar":"Zaid Alma'ayah","title_ar":"اشراف","title_en":"Supervision"}]

اللغة

English

المصدر والدورية

اسم المصدر

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

المحتوى والصفحات

عدد الصفحات

0

كلمات الباحثين

Doxorubicin cardiotoxicity Endothelial-to-Mesenchymal transition (EndMT) CYP epoxygenase inhibition PTUPB vascular toxicity mitigation

إشراف وإعداد

الإشراف

Zaid Alma'ayah

الإعداد

Hevna Dhulkifle

الاقتباسات الببليوغرافية