Dapagliflozin attenuates diabetic cardiomyopathy through erythropoietin up-regulation of AKT/JAK/MAPK pathways in streptozotocin-induced diabetic rats.
PURPOSE
This study was designed to investigate the mechanism of Dapagliflozin (Dapa) cardioprotection against diabetic cardiomyopathy (DCM). Structural and functional changes in the heart as well as decrease of erythropoietin (EPO) levels were reported in DCM. EPO simultaneously activates three pathways: the Janus-activated kinase-signal transducer and activator of transcription (JAK2/STAT5), phosphatidylinositol-3-kinase-Akt (PI3K/Akt), and extracellular signal-related kinase (ERK/MAPK) cascades, that result in proliferation and differentiation of cardiac cells.


METHODS AND RESULTS
DCM was induced by a high fat diet for 10 weeks followed by administration of streptozotocin. After confirmation of diabetes, rats were divided randomly to 5 groups: Group 1; normal control group, Group 2; untreated diabetic group and Groups (3-5); diabetic groups received Dapa daily (0.75 mg, 1.5 or 3 mg/Kg, p.o) respectively for a month. At the end of the experiment, full anaesthesia was induced in all rats using ether inhalation and ECG was recorded. Blood samples were collected then rats were sacrificed and their heart were dissected out and processed for biochemical and histopathological studies. Untreated diabetic rats showed abnormal ECG pattern, elevation of serum cardiac enzymes, decrease EPO levels, downregulation of P-Akt, P-JAK2 and pMAPK pathways, abnormal histological structure of the heart and increase immunostaining intensity of P53 and TNF α in the cardiomyocytes. Dapa in a dose dependent manner attenuated the alterations in the previously mentioned parameters.


CONCLUSION
The cardioprotective effect of Dapa could be mediated by increasing EPO levels and activation of P-Akt, P-JAK2 and pMAPK signalling cascades which in turn decrease apoptosis.
['El-Sayed|Nora|N|', 'Mostafa|Yasser M|YM|', 'AboGresha|Noha M|NM|', 'Ahmed|Amal A M|AAM|', 'Mahmoud|Islam Z|IZ|', 'El-Sayed|Norhan M|NM|']
D000818:Animals D001559:Benzhydryl Compounds D002316:Cardiotonic Agents D003921:Diabetes Mellitus, Experimental D003924:Diabetes Mellitus, Type 2 D058065:Diabetic Cardiomyopathies D004562:Electrocardiography D004921:Erythropoietin D005960:Glucosides D020935:MAP Kinase Signaling System D008297:Male D009206:Myocardium D017208:Rats, Wistar D013311:Streptozocin
Dapagliflozin Diabetic cardiomyopathy Erythropoietin AKT/JAK/MAPK pathways