Abstract
BackgroundEmpagliflozin (empa), a selective sodium–glucose cotransporter (SGLT)2 inhibitor, reduced cardiovascular mortality and hospitalization for heart failure in patients with type 2 diabetes at high cardiovascular risk independent of glycemic control. The cardiovascular protective effect of empa was evaluated in an experimental model of metabolic syndrome, the obese ZSF1 rat, and its’ lean control.MethodsLean and obese ZSF1 rats were either non-treated or treated with empa (30 mg/kg/day) for 6 weeks. Vascular reactivity was assessed using mesenteric artery rings, systolic blood pressure by tail-cuff sphygmomanometry, heart function and structural changes by echocardiography, and protein expression levels by Western blot analysis.ResultsEmpa treatment reduced blood glucose levels from 275 to 196 mg/dl in obese ZSF1 rats whereas normoglycemia (134 mg/dl) was present in control lean ZSF1 rats and was unaffected by empa. Obese ZSF1 rats showed increased systolic blood pressure, and blunted endothelium-dependent relaxations associated with the appearance of endothelium-dependent contractile responses (EDCFs) compared to control lean rats. These effects were prevented by the empa treatment. Obese ZSF1 rats showed increased weight of the heart and of the left ventricle volume without the presence of diastolic or systolic dysfunction, which were improved by the empa treatment. An increased expression level of senescence markers (p53, p21, p16), tissue factor, VCAM-1, SGLT1 and SGLT2 and a down-regulation of eNOS were observed in the aortic inner curvature compared to the outer one in the control lean rats, which were prevented by the empa treatment. In the obese ZSF1 rats, no such effects were observed. The empa treatment reduced the increased body weight and weight of lungs, spleen, liver and perirenal fat, hyperglycemia and the increased levels of total cholesterol and triglycerides in obese ZSF1 rats, and increased blood ketone levels and urinary glucose excretion in control lean and obese ZSF1 rats.ConclusionEmpa reduced glucose levels by 28% and improved both endothelial function and cardiac remodeling in the obese ZSF1 rat. Empa also reduced the increased expression level of senescence, and atherothrombotic markers at arterial sites at risk in the control lean, but not obese, ZSF1 rat.
Highlights
Empagliflozin, a selective sodium–glucose cotransporter (SGLT)2 inhibitor, reduced cardiovas‐ cular mortality and hospitalization for heart failure in patients with type 2 diabetes at high cardiovascular risk inde‐ pendent of glycemic control
Effect of empagliflozin treatment on metabolic parameters in ZSF1 rats Plasma parameters have indicated an increased level of glycemia, plasma proteins and albumin, Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline phosphatase (ALP) whereas plasma creatinine and bilirubin were decreased in the obese ZSF1 group compared to the lean control group (Table 1)
The major findings of the present study indicate that the selective SGLT2 inhibitor empagliflozin improves systolic blood pressure, heart remodeling and endothelial dysfunction in an experimental model of metabolic syndrome with Heart failure with preserved ejection fraction (HFpEF), the ZSF1 rat
Summary
Empagliflozin (empa), a selective sodium–glucose cotransporter (SGLT) inhibitor, reduced cardiovas‐ cular mortality and hospitalization for heart failure in patients with type 2 diabetes at high cardiovascular risk inde‐ pendent of glycemic control. Metabolic syndrome is a critical health state comprising central obesity, dyslipidemia, hypertension, and glucose intolerance that carries increased risk for both type 2. One of the earliest impact of hyperglycemia on the cardiovascular system leads to the induction of an endothelial dysfunction characterized by a reduced nitric oxide (NO) component and often endothelium-dependent hyperpolarization (EDH) component, and the induction of endothelium-dependent contractile responses (EDCFs) [8,9,10,11,12,13,14]. The fact that the selective expression of the senescence marker p53 in the endothelium leads to diminished endothelium-dependent relaxations and NO formation in aortic rings of rats [17] suggests that the induction of cellular senescence acts as a critical upstream signaling pathway to promote endothelial dysfunction
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