The SGLT-2 Inhibitor Dapagliflozin Has a Therapeutic Effect on Atherosclerosis in Diabetic ApoE^−/−Mice

Abstract

Background. Our study aimed to observe the effect of sodium glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin on diabetic atherosclerosis and investigate the subsequent mechanism. Methods. Aortic atherosclerosis was induced in streptozotocin induced diabetic ApoE−/− mice by feeding with high-fat diet, and dapagliflozin was administrated intragastrically for 12 weeks as treatment. Effects of dapagliflozin on indices of glucose and fat metabolism, IL-1β, IL-18, NLRP3 protein levels, and the reactive oxygen species (ROS) were measured. The atherosclerosis was evaluated by oil red O and hematoxylin-eosin staining. The effects of dapagliflozin on the IL-1β production in culturing primary macrophages of wild type and NLRP3−/− knockout mice were investigated for mechanism analyses. Results. Dapagliflozin treatment showed favorable effects on glucose and fat metabolism, partially reversed the formation of atherosclerosis, inhibited macrophage infiltration, and enhanced the stability of lesion. Also, reduced production of IL-1β, IL-18, NLRP3 protein, and mitochondrial ROS in the aortic tissues was detected with dapagliflozin treatment. In vitro, NLRP3 inflammasome was activated by hyperglucose and hyperlipid through ROS pathway. Conclusions. Dapagliflozin may be of therapeutic potential for diabetic atherosclerosis induced by high-fat diet, and these benefits may depend on the inhibitory effect on the secretion of IL-1β by macrophages via the ROS-NLRP3-caspase-1 pathway.

Lansoprazole enhances the antidiabetic effect of dapagliflozin in fortified diet‐fed streptozotocin‐treated diabetic rats

“…[ 52 ] Moreover, the treatment of insulin‐resistant diabetic rats with DAPA or LPZ reduced the serum levels of FFAs, thereby contributing to the insulin‐sensitizing effects of both tested compounds. These results are in agreement with those shown by the previous study [ 53 ] that reported that treatment with DAPA significantly lowered the FFAs levels in diabetic ApoE −/− mice. To the best of our knowledge, the effect of LPZ on FFAs levels has not been previously demonstrated.…”

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

“…DAPA-mediated attenuation of TNFα-induced NFκB mRNA expression implicates DAPA in transcriptional regulation, a novel observation, and in keeping with recently identified 'off target' effects involving activation of cell signalling pathways independent of SGLT-2 by other members of the SGLT-2 class of agents. 5,15 Endothelial cell dysfunction is identified as a significant contributor to early atherogenesis particularly in the vulnerable type 2 diabetic patient population. 16,17 Upregulation of adhesion molecule expression is a marker of endothelial cell dysfunction and a precursor to the development of atherosclerosis.…”

“…Indeed, recent pre-clinical studies support our preliminary observations with identification of reduced atherosclerotic burden in diabetic ApoE −/− mice treated with DAPA with no significant reductions in non-diabetic ApoE −/− mice. 4,5 However, in vitro and in vivo attenuation in vascular peptide expression, improvements in endothelial function, non-significant reductions in weight together with previously documented attenuation of expression of inflammatory mediators and molecules including NFκB and interleukin-1 (IL-1)β in the non-diabetic ApoE −/− mouse model 5 may all combine to produce reductions in atherosclerotic disease burden over extended time periods independently of improvements in hyperglycaemia.…”

Bonus Effects of Antidiabetic Drugs: Possible Beneficial Effects on Endothelial Dysfunction, Vascular Inflammation and Atherosclerosis

“…Dapagliflozin also reduces aortic macrophages infiltration and ROS generation and favours atherosclerotic plaque stabilization. In vitro , dapagliflozin reduces inflammasome activation and decreases IL‐1β release in bone marrow‐derived macrophages stimulated with high concentrations of glucose and lipids .…”

“…Similarly, Leng et al . observed that ApoE −/− mice treated for 12 weeks with dapagliflozin exhibit less vascular inflammation due to reduced plasma concentrations and vascular expression of the inflammasome components, such as nucleotide‐binding oligomerization domain‐like receptor 3 (NLRP3), IL‐1β and IL‐18. Dapagliflozin also reduces aortic macrophages infiltration and ROS generation and favours atherosclerotic plaque stabilization.…”