Abstract
Aim: The sodium-glucose cotransporter 2 inhibitor (SGLT-2i) suggested a possible anti-atherosclerotic and cardioprotective effects beyond glucose lowering effect. However, further study is needed to prove underlying mechanisms of improve on cardiovascular outcomes by SGLT-2i. Therefore, we investigated possible underlying anti-atherosclerotic effect of SGLT-2i ‘Dapagliflozin’ with diabetic rabbit model by inducing atherosclerosis. Methods: Rabbit divided into two groups (each group/n=10); DA: Diabetic atherosclerosis, DAD: Diabetic atherosclerosis + Dapagliflozin. Dapagliflozin was given for a total of 8 weeks. Atherosclerotic plaques were induced with a high cholesterol (HC) diet and balloon inflation. In vivo intravascular imaging and histological assessment was performed. Results: From the histologic evaluation, atheromatous plaque and lipid accumulation were significantly less developed in the Diabetic atherosclerosis + Dapagliflozin group compared to the Diabetic atherosclerosis group. Significantly less macrophage infiltration and inflammatory proteins expression level was observed in the Diabetic atherosclerosis + Dapagliflozin group. The mRNA and protein level of pro-inflammatory markers such as HMGB1, TNF-α, iNOS, and RAGE were significantly lower in the Diabetic atherosclerosis + Dapagliflozin group. The polarization of M1 macrophages was also significantly lower in the Dapagliflozin treated group. The fibronectin and type IV collagen were less observed in the glomerulus of kidney in the Dapagliflozin treated group. The lipid droplet area and size in the liver of Dapagliflozin treated group was smaller and fewer than those in the non-treated group. Conclusion: These results suggest that dapagliflozin may prevent an acceleration atherosclerosis by reducing a vascular inflammation and modifying the macrophage polarization in diabetic animal model. This preliminary clinical observation demonstrates the therapeutic potential of dapagliflozin in diabetic patients with cardiovascular disease.
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