Supervisors info:
Iωάννα Ανδρεάδου, Αναπλ. Καθηγήτρια του Τομέα Φαρμακευτικής Χημείας, Τμήμα Φαρμακευτικής, Πανεπιστήμιο Αθηνών
Original Title:
Μελέτη της επαγόμενης καρδιοπροστασίας από τον αναστολέα συμμεταφορέων νατρίου-γλυκόζης 2 (SGLT-2), Εμπαγλιφλοζίνη, σε υγιείς μύες.
Translated title:
Study of the induced cardioprotection of the sodium-glucose co-transporter 2 (SGLT-2) inhibitor, Empagliflozin, on healthy mice.
Summary:
The sodium-glucose co-transporter 2 (SGLT-2) inhibitors , are a novel class of agents indicated for the improvement of glycemic control in adults with type 2 diabetes mellitus (T2DM). By enhancing glucose excretion through the urinary tract and reducing plasma glucose levels through an insulin-independent mechanism, they face many of the restrictions of other available therapieutic agents for T2DM such as hypoglycemia and weight gain. SGLT2 inhibitors also exhibit other important non-glycemic effects such as blood pressure lowering, body weight reduction and favorably altering fat distribution.
Empagliflozin one of the newest members of this class, in the EMPA-REG clinical trial, has shown a significant reduction in cardiovascular mortality in T2DM patients with established cardiovascular disease. The positive results of this trial led our laboratory research team to investigate the effects of Empagliflozin on myocardial infarction following ischemia / reperfusion injury. Thus, after chronic administration to a diabetic mouse model that was subjected to ischemia / reperfusion surgical intervention, Empagliflozin showed significantly reduced infarct size compared to the control group, and further investigation showed that its cardioprotective effect is likely to be due to activation of the STAT-3 transcription factor independently of the RISK signaling pathway and AMPK kinase. Also, treatment with Empagliflozin, enhanced cell viability after hypoxia / reoxygenation injury (Andreadou et al., 2017).
In the present study, for further investigation of the cardioprotective effects of Empagliflozin, protocols of acute and chronic administration were designed and executed on a healthy experimental mouse model, as well as an in vitro protocol investigating the viability of HUVEC and H9C2 cells in the presence of Empagliflozin and the inhibitor of STAT-3 activation, STATTIC. Macroscopic assessment of myocardial infarct size, western blot analysis of myocardial tissues, and cell viability assay using MTT technique were performed. Results showed that acute administration of Empagliflozin in the healthy experimental model had no effect on the extent of myocardial infarction. In contrast, chronic administration resulted in a statistically significant reduction in infarct size and increased activation of the STAT-3 transcription factor without any changes in the activation of ERK1 / 2, AMPK, and the anti-oxidant MnSOD2 compared to the control group. In addition, the results of the MTT analysis showed that Empagliflozin enhances cell viability while the STAT-3 activation inhibitor significantly reduces it. The co-treatment of STATTIC and Empagliflozin partly restores cell viability, indicating a potential involvement of STAT-3 in the Empagliflozin-induced protection mechanism.
Keywords:
sodium-glucose co-transporter 2 inhibitors, cardioprotection, ischemia, reperfusion, infarction
