Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: A potential mechanism for inhibition of atherogenesis

Abstract

Background: Sodium glucose transporter type 2 inhibitors may reduce cardiovascular events in type 2 diabetes. Our study aimed to determine the effect of the sodium glucose transporter type 2 inhibitor dapagliflozin on endothelial cell activation, vasoreactivity and atherogenesis using in vitro and in vivo models and identify associated molecular mechanisms. Methods:In vitro studies utilised human vascular endothelial cells stimulated with tumour necrosis factor α or hyperglycaemic conditions. In vivo studies were performed in C57Bl/6J mice to evaluate direct vasorelaxation responses evoked by acute dapagliflozin administration and acute vaso-protective effects of dapagliflozin on hyperglycaemia-induced endothelial dysfunction. Adult and aged Apolipoprotein E-deficient mice maintained on a high-fat diet were used to investigate endothelial-dependent vascular reactivity and atherogenesis. Dapagliflozin treatment (1.0 mg/kg/day) was administered for 4 weeks. Results:In vitro studies demonstrated dapagliflozin-mediated attenuation of tumour necrosis factor α-and hyperglycaemiainduced increases in intercellular adhesion molecule-1, vascular cell adhesion molecule-1, plasminogen activator inhibitor type 1 and NFκB expression. Acute dapagliflozin administration dose-dependently induced endothelium-independent vasorelaxation. Chronic dapagliflozin treatment improved endothelial function and significantly reduced in vivo vascular adhesion molecule and phospho-IκB expression together with macrophage vessel wall infiltration. Conclusion: These observations identify a potential role for dapagliflozin in the attenuation of atherogenesis and identify anti-inflammatory molecular mechanisms associated with these effects.

Novel Anti-inflammatory Effects of Canagliflozin Involving Hexokinase II in Lipopolysaccharide-Stimulated Human Coronary Artery Endothelial Cells

“…Our data correspond well with previous studies, showing that Cana reduces IL-6 release in IL-1β-stimulated human endothelial cells and in LPS-stimulated macrophages [18,42]. However, the effect of Cana on IL-6 release reduction was absent at a [22,23]. In the present study, we cannot rule out that Empa and Dapa do affect LPS-induced IL-6 release due to the higher variations observed in the experiments using Empa or Dapa.…”

“…Recent data suggest that direct, SGLT2 unrelated, cardiovascular actions of SGLT2 inhibitors account, at least in part, for the reported cardiovascular benefits [16][17][18][19][20][21]. Interestingly, several of these studies suggest an anti-inflammatory mechanism underlying the positive clinical outcomes of SGLT2 inhibitors [18,22,23]. Others report that glucose uptake is hindered by SGLT2 inhibitors in a variety of cell types, including endothelial cells [24][25][26].…”

The SGLT2 Inhibitor Dapagliflozin Significantly Improves the Peripheral Microvascular Endothelial Function in Patients with Uncontrolled Type 2 Diabetes Mellitus

“…Because SGLT2 inhibitors improve the glycemic control via the reduction in the body weight and fat mass (2), SGLT2 inhibitors may be able to achieve cardiovascular benefits by improving the endothelial function, accompanied by a decrease in the abdominal fat mass and an increase in the plasma adiponectin levels. Recent experimental approaches to examining the mechanism underlying the effects of SGLT2 inhibitors on the vascular function have suggested that the effects of SGLT2 inhibitors on the endothelial function may be independent of a reduction in fat (34,35). Further studies are required to clarify the precise mechanisms underlying the effects of SGLT2 inhibitors on the endothelial function.…”

“…In in vivo animal models, dapagliflozin treatment (35), empagliflozin treatment (39), and ipragliflozin treatment (34) improved the endothelial function. However, we lack sufficient clinical data at present regarding the SGLT2 inhibitor-induced improvement in the endothelial function as a drug class effect.…”

Empagliflozin Protects Atherosclerosis Progression by Modulating Lipid Profiles and Sympathetic Activity

“…Our results were consistent with these studies. It was reported that SGLT2 inhibitors could inhibit the activation of NLRP3 in ammasome [17], reduce the secretion of vasoconstrictive eicosanoids and pro-in ammatory chemokines in the vasculature [15,18], playing an anti-in ammation role. A study showed that empagli ozin prevented the development of atherosclerosis and reduced in ammation and fat deposition in non-diabetic ApoE-/-mice [8].…”