Anti-Inflammatory Effect for Atherosclerosis Progression by Sodium-Glucose Cotransporter 2 (SGLT-2) Inhibitor in a Normoglycemic Rabbit Model

Abstract

Background and Objectives: We sought to investigate an anti-atherosclerotic and antiinflammatory effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in normoglycemic atherosclerotic rabbit model. Methods: Male New Zealand white rabbits (n=26) were fed with a 1% high-cholesterol diet for 7 weeks followed by normal diet for 2 weeks. After balloon catheter injury, the rabbits were administered with the Dapagliflozin (1mg/kg/day) or control-medium for 8 weeks (n=13 for each group). All lesions were assessed with angiography, optical coherence tomography (OCT), and histological assessment. Results: Atheroma burden (38.51±3.16% vs. 21.91±1.22%, p<0.01) and lipid accumulation (18.90±3.63% vs. 10.20±2.03%, p=0.047) was significantly decreased by SGLT-2 inhibitor treatment. The SGLT-2 inhibitor group showed lower macrophage infiltration (20.23±1.89% vs. 12.72±1.95%, p=0.01) as well as tumor necrosis factor (TNF)-α expression (31.17±4.40% vs. 19.47±2.10%, p=0.025). Relative area of inducible nitric oxide synthase + macrophages was tended to be lower in the SGLT-2 inhibitor-treated group (1.00±0.16% vs. 0.71±0.10%, p=0.13), while relative proportion of Arg1 + macrophage was markedly increased (1.00±0.27% vs. 2.43±0.64%, p=0.04). As a result, progression of atherosclerosis was markedly attenuated in SGLT-2 inhibitor treated group (OCT area stenosis, 32.13±1.20% vs. 22.77±0.88%, p<0.01). Mechanistically, SGLT-2 treatment mitigated the inflammatory responses in macrophage.

Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics

“… 91 . Similar results were reported in a rabbit model, in which dapagliflozin increased M2 macrophages and inhibited toll-like receptor 4/nuclear factor-kappa B signaling pathway which serve as master regulators of inflammatory responses in macrophages 67 .…”

“…The benefits of dapagliflozin on atherosclerosis have also been demonstrated in experimental animals other than mice. For example, in a rabbit model of atherosclerosis, dapagliflozin was found to exhibit anti-atherosclerotic effects by modulating inflammatory responses (decreased expression of TNF-α, IL-1β, and IL-6) and macrophage polarization (toward M2 macrophages) under non-diabetic conditions 67 .…”

Canagliflozin attenuates isoprenaline-induced cardiac oxidative stress by stimulating multiple antioxidant and anti-inflammatory signaling pathways

“…Canagliflozin reduced cardiac nitro-oxidative stress, ameliorated cardiac ischemia-reperfusion injury (IRI), and improved heart function by stimulating antioxidant and anti-inflammatory signaling 12,17 . Similarly, other members of SGLT2 inhibitors such as empagliflozin and dapagliflozin were also reported to improve cardiovascular function by reducing oxidative stress and inflammation 10,14,[18][19][20][21] .…”

“…Proposed mechanisms for cardiovascular benefits of canagliflozin include improvement of cardiac metabolism and diastolic function, reduction of vascular stiffness, and an overall reduction of blood pressure 5 – 9 . A growing body of evidence suggests that canagliflozin possess antioxidant and anti-inflammatory actions in various cell-based and animal models 10 – 14 . Canagliflozin was shown to reduce vascular inflammation and atherosclerosis by suppressing vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemotaxis protein-1 (MCP-1) expression 15 .…”

Heart Failure with Preserved Ejection Fraction: the Major Unmet Need in Cardiology

“…SGLT-2 inhibitors have demonstrated convincing reductions in the incidence and risks of HF in patients with DM. 52) 53) 54) 55) Now, studies are underway to prove the beneficial effects of SGLT-2 inhibitors in overt HF patients with or without DM.…”