背景:阿霉素(DOX)是一种有效的化学疗法,广泛用于治疗各种肿瘤疾病。然而,由于DOX对心血管系统的潜在毒性作用,其临床应用受到限制。因此,确定与这种毒性相关的通路可能有助于降低化疗风险并改善癌症患者的生活质量。最近的研究表明,内皮-间质转化(EndMT)和内皮毒性参与了DOX诱导的心血管毒性的发病机制。然而,分子机制尚不清楚。鉴于花生四烯酸和相关的细胞色素P450(CYP)环氧合酶已参与内皮和心血管功能,我们旨在研究抑制CYP环氧合酶在体外和体内对DOX诱导的EndMT和心血管毒性的影响。
结果:要对此进行测试,用DOX处理人内皮细胞,有或没有CYP环氧合酶抑制剂,MSPPOH.我们还在斑马鱼DOX诱导的心脏毒性模型中研究了MSPPOH对心血管系统的影响。我们的结果表明,MSPPOH加剧了DOX诱导的EndMT,炎症,氧化应激,以及内皮细胞的凋亡。此外,我们还显示MSPPOH增加了心脏水肿,血管血流速度降低,在我们的DOX诱导的心脏毒性斑马鱼模型中,EndMT和心脏损伤标志物的表达恶化。
结论:我们的数据表明,选择性CYP环氧合酶抑制剂,MSPPOH,诱导EndMT和内皮毒性有助于DOX诱导的心血管毒性。
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.
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.
CONCLUSIONS: Our data indicate that a selective CYP epoxygenase inhibitor, MSPPOH, induces EndMT and
endothelial toxicity to contribute to DOX-induced cardiovascular toxicity.