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

Abstract

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.

Tofogliflozin Delays Portal Hypertension and Hepatic Fibrosis by Inhibiting Sinusoidal Capillarization in Cirrhotic Rats

“…Notably, we found that SGLT2 expression was higher in LSECs than in hepatocytes or Ac-hHSCs, and its expression increased as capillarization progressed. SGLT2 is mainly expressed in the renal proximal tubules, but many studies have recently revealed SGLT2 expression in vascular endothelial cells, as evidenced by the cardiovascular protective effects of SGLT2-Is [ 16 , 21 , 34 ]. Thus, it is possible that tofogliflozin predominantly affected capillaries in hLSECs through SGLT2 in the cirrhotic liver.…”

“…Recent case reports have demonstrated that SGLT2-Is reduce ascites and peripheral edema in patients with liver cirrhosis, which can be attributed to their action on endothelial cells [ 18 ]. Several studies have shown that SGLT2-Is can directly affect endothelial function independently of glycemic status and through various pathways, resulting in improved vasodilation via increased NO production and bioavailability [ 19 , 20 , 21 ]. Moreover, SGLT2-Is also repressed ET-1 expression while enhancing eNOS activation in a mouse myocardial ischemia–reperfusion injury model [ 22 ].…”