Role of hypoxia inducible factor/vascular endothelial growth factor/endothelial nitric oxide synthase signaling pathway in mediating the cardioprotective effect of dapagliflozin in cyclophosphamide-induced cardiotoxicity.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: DAP could reduce CP cardiotoxicity based upon its ability to modulate SGLT2 and HIF1α/VEGF/eNOS signaling pathway.

Sacubitril/valsartan cardioprotective effect against cisplatin-induced cardiotoxicity via modulation of VEGF/eNOS and TLR4/TNFα/IL6 signalling pathways.

OBJECTIVES: Drug-induced cardiac injury is a potentially preventable cause of heart failure. Cisplatin (CIS) is a widely used chemotherapeutic agent complicated with cardiotoxicity that limits its clinical application so we aimed to evaluate the suspected cardioprotective effect of sacubitril/valsartan (Sac/Val) against CIS cardiotoxic injury. METHODS: Forty male rats of Wistar albino species were divided into four groups. group I received the vehicle; group II was given the vehicle plus CIS (10 mg/kg) single i.p. on fifth day; group III was given Sac/Val (30 mg/kg/d) orally for 7 days plus CIS (10 mg/kg) single i.p. on fif5th day; group IV was given the same as group III plus nitro-ω-L-arginine (L-NNA) (25 mg/kg/d) orally for 7 days. KEY FINDINGS: CIS-induced cardiotoxicity and L-NNA co-administered group showed significant increases in cardiac enzymes, toxic histopathological features, elevated heart weights, angiotensin II (Ang II), neprilysin, malondialdehyde (MDA), inflammatory mediators, blood pressure (BP) and caspase 3 expressions, but there are significant decreases in the antioxidant parameters, vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). However, the co-administration of Sac/Val could ameliorate these changes of CIS. CONCLUSION: Sac/Val has an important cardioprotective effect against CIS cardiotoxicity with the involvement of eNOS.