Department of Pharmacology, Faculty of Medicine, Minia University, 61511, El-Minia, Egypt.
Department of Pharmacology, Faculty of Medicine, Minia University, 61511, El-Minia, Egypt.
Toxicology. 2022 Jan 15;465:153042. doi: 10.1016/j.tox.2021.153042. Epub 2021 Nov 17.
5-fluorouracil (5-FU) is a widely used chemotherapeutic agent but cardiotoxicity challenges its clinical usefulness. Thus, searching for more cardioprotective drugs is highly required to prevent the accompanied cardiac hazards. Up to date, the different mechanisms involved in 5-FU cardiotoxicity are still unclear and there is no evaluation of bosentan's role in controlling these cardiac complications. This forced us to deeply study and evaluate the possible cardiopreserving properties of bosentan and different mechanisms involved in mediating it. 32 Wistar albino rats were included in our experiment and induction of cardiotoxicity was performed via administration of 5-FU (150 mg/kg) on 5th day of the experiment by intraperitoneal (i.p.) injection with or without co-administration of bosentan (50 mg/kg/day) orally for 7days. Our data revealed that 5-FU could induce cardiotoxicity which was detected as significant increases of troponin I, lactate dehydrogenase (LDH), creatine kinase- MB (CK-MB), endothelin receptors, malondialdehyde (MDA), toll like receptor4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor kappa B (NFκB), and caspase 3 levels. However, there is marked decrease in endothelial nitric oxide synthase (eNOS), reduced glutathione (GSH) and total antioxidant capacity (TAC). In addition, the histopathological examination showed severe toxic features of cardiac injury. Interestingly, co-administration of bosentan could ameliorate 5-FU-induced cardiotoxicity via improving the detected biochemical and histopathological changes besides modulation of TLR4/MyD88/NFκB signaling pathway, eNOS, and endothelin receptors. Bosentan had a significant cardioprotective effect against 5-FU induced cardiac damage. This effect may be attributed to its ability to inhibit endothelin receptors, stimulates eNOS, anti-oxidant, anti-inflammatory, anti-apoptotic properties with modulation of TLR4/MyD88/NFκB signaling pathway.
5-氟尿嘧啶（5-FU）是一种广泛应用的化疗药物，但它的心脏毒性限制了其临床应用。因此，迫切需要寻找更多的心脏保护药物来预防伴随的心脏危害。迄今为止，5-FU 心脏毒性的不同机制仍不清楚，也没有评估波生坦在控制这些心脏并发症中的作用。这迫使我们深入研究和评估波生坦的可能心脏保护特性及其介导的不同机制。我们的实验纳入了 32 只 Wistar 白化大鼠，通过腹腔注射 5-FU（150mg/kg）在实验的第 5 天诱导心脏毒性，或同时给予波生坦（50mg/kg/天）口服 7 天。我们的数据显示，5-FU 可诱导心脏毒性，表现为肌钙蛋白 I、乳酸脱氢酶（LDH）、肌酸激酶-MB（CK-MB）、内皮素受体、丙二醛（MDA）、Toll 样受体 4（TLR4）、髓样分化初级反应 88（MyD88）、核因子 kappa B（NFκB）和半胱氨酸天冬氨酸蛋白酶 3（caspase 3）水平显著升高。然而，内皮型一氧化氮合酶（eNOS）、还原型谷胱甘肽（GSH）和总抗氧化能力（TAC）显著降低。此外，组织病理学检查显示心脏损伤有严重的毒性特征。有趣的是，波生坦的共同给药可以通过改善检测到的生化和组织病理学变化来改善 5-FU 诱导的心脏毒性，此外还可以调节 TLR4/MyD88/NFκB 信号通路、eNOS 和内皮素受体。波生坦对 5-FU 诱导的心脏损伤具有显著的心脏保护作用。这种作用可能归因于其抑制内皮素受体的能力，刺激 eNOS、抗氧化、抗炎、抗凋亡的特性，并调节 TLR4/MyD88/NFκB 信号通路。
