Abstract
Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus (DM). One of the hallmarks of the DCM is enhanced oxidative stress in myocardium. The aim of this study was to research the underlying mechanisms involved in the effects of dapagliflozin (Dap) on myocardial oxidative stress both in streptozotocin-induced DCM rats and rat embryonic cardiac myoblasts H9C2 cells exposed to high glucose (33.0 mM). In in vivo studies, diabetic rats were given Dap (1 mg/ kg/ day) by gavage for eight weeks. Dap treatment obviously ameliorated cardiac dysfunction, and improved myocardial fibrosis, apoptosis and oxidase stress. In in vitro studies, Dap also attenuated the enhanced levels of reactive oxygen species and cell death in H9C2 cells incubated with high glucose. Mechanically, Dap administration remarkably reduced the expression of membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits gp91phox and p22phox, suppressed the p67phox subunit translocation to membrane, and decreased the compensatory elevated copper, zinc superoxide dismutase (Cu/Zn-SOD) protein expression and total SOD activity both in vivo and in vitro. Collectively, our results indicated that Dap protects cardiac myocytes from damage caused by hyperglycemia through suppressing NADPH oxidase-mediated oxidative stress.
Highlights
Diabetes mellitus (DM) with hyperglycemia as the main feature has become a global public health problem (Wild, 2004)
The blood glucose of the STZinduced diabetic group (STZ) rats was notably higher compared with the control group (Con) rats, and Dap treatment significantly reduced the level of blood glucose
With the results acquired from the high fat diet and low dose STZ-induced diabetic rats, ob/ob mice, and db/db mice (Ye et al, 2017; Giuliani, 2019; Arow et al, 2020; Chen et al, 2020), the present study demonstrated that treatment with Dap for 8 weeks successfully improved cardiac dysfunction and reduced myocardial fibrosis and apoptosis in STZ-induced diabetic mice
Summary
Diabetes mellitus (DM) with hyperglycemia as the main feature has become a global public health problem (Wild, 2004). Dapagliflozin (Dap), a highly selective SGLT2 inhibitor, is used as an effective treatment against type 2 DM and prevents the development of diabetic nephropathy (Wheeler et al, 2020; Wheeler et al, 2021). Arow et al (2020) reported that Dap decreases myocardial inflammation and reactive oxygen species (ROS) production in db/db type 2 DM mice and isolated cardiomyocytes. These data indicate that Dap is a possible therapeutic agent in the treatment of DCM through anti-inflammation and anti-oxidative stress. The molecular mechanisms of Dap treatment resulting in the decrease of myocardial ROS levels has not been completely elucidated
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