PMID- 37526264
OWN - NLM
STAT- MEDLINE
DCOM- 20231102
LR  - 20231102
IS  - 1477-0903 (Electronic)
IS  - 0960-3271 (Linking)
VI  - 42
DP  - 2023 Jan-Dec
TI  - 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.
PG  - 9603271231193392
LID - 10.1177/09603271231193392 [doi]
AB  - 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 alpha 
      (HIF1alpha)/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-omega-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 (TNFalpha), HIF1alpha, 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 
      HIF1alpha/VEGF/eNOS signaling pathway.
FAU - Mahmoud Refaie, Marwa Monier
AU  - Mahmoud Refaie MM
AUID- ORCID: 0000-0003-0216-5020
AD  - Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, 
      Egypt. RINGGOLD: 68877
FAU - Bayoumi, Asmaa Ma
AU  - Bayoumi AM
AD  - Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, 
      Egypt. RINGGOLD: 68843
FAU - Mokhemer, Sahar Ahmed
AU  - Mokhemer SA
AD  - Department of Histology and Cell Biology, Faculty of Medicine, Minia University, 
      El-Minia, Egypt. RINGGOLD: 68843
FAU - Shehata, Sayed
AU  - Shehata S
AD  - Department of Cardiology, Faculty of Medicine, Minia University, El-Minia, Egypt. 
      RINGGOLD: 68877
FAU - Abd El-Hameed, Nahla Mohammed
AU  - Abd El-Hameed NM
AD  - Department of Histology and Cell Biology, Faculty of Medicine, Minia University, 
      El-Minia, Egypt. RINGGOLD: 68843
LA  - eng
PT  - Journal Article
PL  - England
TA  - Hum Exp Toxicol
JT  - Human & experimental toxicology
JID - 9004560
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - 1ULL0QJ8UC (dapagliflozin)
RN  - 0 (Antioxidants)
RN  - 0 (Sodium-Glucose Transporter 2)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - 8N3DW7272P (Cyclophosphamide)
RN  - 31C4KY9ESH (Nitric Oxide)
SB  - IM
MH  - Rats
MH  - Animals
MH  - Male
MH  - *Cardiotoxicity/drug therapy
MH  - *Vascular Endothelial Growth Factor A/metabolism
MH  - Nitric Oxide Synthase Type III/metabolism
MH  - Antioxidants/pharmacology
MH  - Sodium-Glucose Transporter 2/metabolism/pharmacology/therapeutic use
MH  - Nitric Oxide Synthase/metabolism
MH  - Signal Transduction
MH  - Rats, Wistar
MH  - Cyclophosphamide/toxicity/therapeutic use
MH  - Hypoxia
MH  - Nitric Oxide/metabolism
OTO - NOTNLM
OT  - Dapagliflozin
OT  - cardiotoxicity
OT  - cyclophosphamide
OT  - endothelial nitric oxide synthase
OT  - vascular endothelial growth factor
EDAT- 2023/08/01 13:09
MHDA- 2023/08/01 13:10
CRDT- 2023/08/01 07:33
PHST- 2023/08/01 13:10 [medline]
PHST- 2023/08/01 13:09 [pubmed]
PHST- 2023/08/01 07:33 [entrez]
AID - 10.1177/09603271231193392 [doi]
PST - ppublish
SO  - Hum Exp Toxicol. 2023 Jan-Dec;42:9603271231193392. doi: 
      10.1177/09603271231193392.