Role of Dapagliflozin and Liraglutide on Diabetes-Induced Cardiomyopathy in Rats: Implication of Oxidative Stress, Inflammation, and Apoptosis

Abstract

The current study aims to assess the protective effects of dapagliflozin (Dapa; a sodium-glucose cotransporter-2 inhibitor) and/or liraglutide (Lira; a glucagon-like peptide 1 agonist) in an experimental model of diabetic cardiomyopathy (DCM). A single dose of streptozotocin (STZ) was administrated to male Sprague–Dawley rats by intraperitoneal injection at a dose of 50 mg/kg to induce diabetes mellitus (DM). Dapa (1 mg/kg, orally), Lira (0.4 mg/kg, s.c.), and Dapa–Lira combination were administrated for 8 weeks once-daily. Blood samples were evaluated for glucose level and biochemical markers of cardiac functions. Cardiac tissue was dissected and assessed for redox homeostasis (malondialdehyde (MDA), glutathione (GSH), and catalase (CAT)), pro-inflammatory mediators (NF-κB and tumor necrosis factor-α (TNF-α)), and apoptotic effectors (caspase-3). Moreover, the effect of treatments on the cardiac cellular structure was studied. Dapa and/or Lira administration resulted in significant improvement of biochemical indices of cardiac function. Additionally, all treatment groups demonstrated restoration of oxidant/antioxidant balance. Moreover, inflammation and apoptosis key elements were markedly downregulated in cardiac tissue. Also, histological studies demonstrated attenuation of diabetes-induced cardiac tissue injury. Interestingly, Dapa–Lira combination treatment produced a more favorable protective effect as compared to a single treatment. These data demonstrated that Dapa, Lira, and their combination therapy could be useful in protection against DM-accompanied cardiac tissue injury, shedding the light on their possible utilization as adjuvant therapy for the management of DM patients.

Dapagliflozin, Liraglutide, and Their Combination Attenuate Diabetes Mellitus-Associated Hepato-Renal Injury—Insight into Oxidative Injury/Inflammation/Apoptosis Modulation

“…Noteworthy, El-Shafey et al [ 23 ] reported an additive impact of combined Dapa and Lira treatment on DM-induced oxidative injury and DM-induced cardiomyopathy, which gives further credence to our observations in the current study.…”

“…Interestingly, in this study, combined Dapa/Lira treatment exerted an additive impact on the suppression of the hepatic–renal expression of the inflammatory milieu NF-κB/TNF-α; the observations of El-Shafey et al [ 23 ] give credence to these observations.…”

“…Moreover, Dapa attenuated oxidative-injury-induced cell injury in human proximal tubular cells by reducing cytosolic and mitochondrial ROS production and altering the Ca 2+ dynamics [ 22 ]. Moreover, Dapa has recently been reported to attenuate DM-induced cardiomyopathy, with an underlying impact on antioxidants [ 23 ].…”

Dapagliflozin Protects Methamphetamine-Induced Cardiomyopathy by Alleviating Mitochondrial Damage and Reducing Cardiac Function Decline in a Mouse Model

“…DAPA reportedly improves cardiac morphology and function in a diabetic cardiomyopathy model and a doxorubicin cardiomyopathy model by enhancing cardiac energy metabolism and decreasing oxidative stress and myocardial cell apoptosis ( El-Shafey et al, 2022 ) ( Chang et al, 2022 ). However, whether DAPA can ameliorate METH-induced oxidative stress has not been studied.…”

“…DAPA has been demonstrated to protect against apoptosis in ischemia-reperfusion models by inhibiting caspase3 activation ( Tanajak et al, 2018 ). It also downregulates key molecules in the apoptosis pathway in a diabetic cardiomyopathy model ( El-Shafey et al, 2022 ). However, the effect of DAPA on METH-induced cardiomyocyte apoptosis has not been revealed.…”