الفهرس | Only 14 pages are availabe for public view |
Abstract Abstract Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus associated with structural and functional changes in the heart. Dapagliflozin (DAPA) was shown to confer cardioprotection; however, its exact mechanisms are not fully elucidated. Erythropoietin (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. In this study, DCM was induced by a high-fat diet for 10 weeks, followed by administration of streptozotocin, (30mg/kg , I.P). After confirmation of diabetes, rats were divided randomly into 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 anesthesia was induced in all rats using ether inhalation, and ECG was recorded. Blood samples were collected, then rats were sacrificed, and their hearts 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 could improve ECG pattern, decrease the myocardial and left ventricular weight indexes, mortality rate, and serum levels of cardiac enzymes. It also could improve the histopathological structure of the heart and reorganize of the cardiac myofibers. Moreover, DAPA could attenuate cardiac fibrosis also could ameliorate immunohistochemical staining of TNF alpha and p53. 2 Eventually, leading to, respectively, decrease inflammation and apoptosis in cardiac cells . The cardioprotective effect of DAPA could be mediated by increasing EPO levels and activation of P-Akt, P-JAK2, and pMAPK signaling cascades, which in turn decrease apoptosis. |