Effects of sodium-glucose co-transporter protein type 2 blockade on cardiac remodeling in rats with diabetes mellitus

Abstract

Diabetes mellitus (DM) is a metabolic disorder of multiple etiology characterized by chronic hyperglycemia, which causes disturbances in the metabolism of carbohydrates, fats and proteins, resulting from defects in secretion and/or insulin action. Besides being responsible for damage in multiple organs (nerves, kidneys and eyes), DM is one of the main risk factors for the development of coronary atherosclerosis, as well as cause of non atherogenic myocardial disease, diabetic cardiomyopathy. Type 1 and type 2 diabetes increases from 2 to 6 times the risk to develop cardiovascular disease. Evidences suggest benefits of aggressive glycemic control, which may reduce the risk of complications associated with DM. A new class of antidiabetic drugs aims to block the sodium-glucose co-transporter protein type 2 (SGLT2). Thus, blockade of the protein results in a consequent decrease of hyperglycemia by reducing reabsorption of glucose and increasing urinary excretion. However, in addition to its possible side effects, there are few studies using this new class of drugs, mainly evaluating their influence on the heart. Therefore, the aim is to analyze the effects of sodium-glucose co-transporter protein type 2 (dapagliflozin - DAPA) blockade on cardiac remodeling in rats with diabetes mellitus. Methods: male Wistar rats with 400 g will be divided into four groups: control (CTL, n=15); CTL+DAPA (n=15); DM (n=15); DM+DAPA (n=15). DM will be induced by streptozotocin (40 mg/kg, i.p., single dose). CTL+DAPA and DM+DAPA groups will receive DAPA (30 mg/kg/day, added in the chow) for 8 weeks. In vivo cardiac structures and functions will be assessed by echocardiogram. In vitro left ventricle (LV), right ventricle and atria weights will be measured. Samples of these structures, liver and lung will be used to calculate the wet/dry weight ratio. LV tissue samples will be obtained to measure myocyte diameters, interstitial collagen fraction, and hydroxyproline concentration. Left ventricular types I and III collagen and lysyl oxidase protein expressions will be evaluated by western blotting. Oxidative stress will be evaluated by measuring in serum and cardiac tissue the activity of superoxide dismutase, glutathione peroxidase, catalase, and lipid hydroperoxide concentration. The measure of thydrophilic antioxidant capacity will be performed in serum. Quantification of advanced glycation end products (AGEs) in LV will be performed by immunohistochemistry. Statistics: Comparisons will be performed by ANOVA - 2x2 factorial (p<0.05). (AU)