Mahmoud Refaie Marwa Monier, Bayoumi Asmaa Ma, Mokhemer Sahar Ahmed, Shehata Sayed, Abd El-Hameed Nahla Mohammed
Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, Egypt.
Hum Exp Toxicol. 2023 Jan-Dec;42:9603271231193392. doi: 10.1177/09603271231193392.
Cyclophosphamide (CP) is a commonly used chemotherapeutic and immunosuppressive alkylating agent. However, cardiac adverse effects of CP interfere with its clinical benefit. Cardio-oncology research is currently an important issue and finding effective cardiopreserving agents is a critical need. For the first time, we aimed to detect if dapagliflozin (DAP) could ameliorate CP-induced cardiac injury and investigated the role of hypoxia inducible factor α (HIF1α)/vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) pathway.
Forty male Wistar albino rats were included in the current model. Studied groups are: control group; CP-induced cardiotoxicity group; CP group treated with DAP; CP group treated with DAP and administered a nitric oxide synthase inhibitor; nitro-ω-L-arginine (L-NNA) before DAP to explore the role of eNOS.
Our data revealed that CP could induce cardiac damage as manifested by significant increases in cardiac enzymes, blood pressure, malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), HIF1α, sodium glucose co-transporter 2 (SGLT2) and cleaved caspase-3 levels with toxic histopathological changes. However, there are significant decreases in reduced glutathione (GSH), total antioxidant capacity (TAC), VEGF, and eNOS. On the opposite side, co-administration of DAP showed marked improvement of CP-induced cardiac damage that may be due to its ability to inhibit SGLT2, antioxidant, anti-inflammatory and anti-apoptotic properties. Results showed decreasing the cardioprotective effect of DAP on administration of L-NNA, reflecting the critical effect of eNOS in mediating such protection.
DAP could reduce CP cardiotoxicity based upon its ability to modulate SGLT2 and HIF1α/VEGF/eNOS signaling pathway.
环磷酰胺（CP）是一种常用的化疗和免疫抑制烷化剂。然而，CP的心脏不良反应会影响其临床疗效。心脏肿瘤学研究是当前的一个重要问题，寻找有效的心脏保护剂至关重要。我们首次旨在检测达格列净（DAP）是否能改善CP诱导的心脏损伤，并研究缺氧诱导因子α（HIF1α）/血管内皮生长因子（VEGF）/内皮型一氧化氮合酶（eNOS）通路的作用。
本模型纳入40只雄性Wistar白化大鼠。研究组包括：对照组；CP诱导的心脏毒性组；用DAP治疗的CP组；用DAP治疗并给予一氧化氮合酶抑制剂的CP组；在给予DAP前给予硝基-ω-L-精氨酸（L-NNA）以探讨eNOS的作用。
我们的数据显示，CP可导致心脏损伤，表现为心脏酶、血压、丙二醛（MDA）、肿瘤坏死因子α（TNFα）、HIF1α、钠葡萄糖协同转运蛋白2（SGLT2）和裂解的半胱天冬酶-3水平显著升高，并伴有毒性组织病理学改变。然而，还原型谷胱甘肽（GSH）、总抗氧化能力（TAC）、VEGF和eNOS显著降低。相反，联合使用DAP可显著改善CP诱导的心脏损伤，这可能归因于其抑制SGLT2的能力、抗氧化、抗炎和抗凋亡特性。结果显示，给予L-NNA后DAP的心脏保护作用减弱，这反映了eNOS在介导这种保护中的关键作用。
DAP可通过调节SGLT2和HIF1α/VEGF/eNOS信号通路降低CP的心脏毒性。
