Canagliflozin Prevents Diabetes-Induced Vascular Dysfunction in ApoE-Deficient Mice

Abstract

Recent studies have demonstrated that selective sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce cardiovascular events, although their mechanism remains obscure. We examined the effect of canagliflozin, an SGLT2i, on atherogenesis and investigated its underlying mechanism. Method: Canagliflozin (30 mg/kg/day) was administered by gavage to streptozotocin-induced diabetic apolipoprotein E-deficient (ApoE /) mice. Sudan IV staining was performed at the aortic arch. Immunostaining, quantitative RT-PCR, and vascular reactivity assay were performed using the aorta. In vitro experiments using human umbilical vein endothelial cells (HUVECs) were also performed. Result: Canagliflozin decreased blood glucose (P 0.001) and total cholesterol (P 0.05) levels. Sudan IV staining showed that 12-week canagliflozin treatment decreased atherosclerotic lesions (P 0.05). Further, 8-week canagliflozin treatment ameliorated endothelial dysfunction, as determined by acetylcholine-induced vasodilation (P 0.05), and significantly reduced the expressions of inflammatory molecules such as ICAM-1 and VCAM-1 in the aorta at the RNA and protein levels. Canagliflozin also reduced the expressions of NADPH oxidase subunits such as NOX2 and p22phox in the aorta and reduced urinary excretion of 8-OHdG, suggesting a reduction in oxidative stress. Methylglyoxal, a precursor of advanced glycation end products, increased the expressions of ICAM-1 and p22phox in HUVECs (P 0.05, both). Methylglyoxal also decreased the phosphorylation of eNOS Ser1177 and Akt but increased the phosphorylation of eNOS Thr495 and p38 MAPK in HUVECs. Conclusion: Canagliflozin prevents endothelial dysfunction and atherogenesis in diabetic ApoE / mice. Antiinflammatory and antioxidative potential due to reduced glucose toxicity to endothelial cells might be its underlying mechanisms. using medical treatment and lifestyle modifications, it is still hard to achieve the goal of reducing blood glucose to an optimal level 4, 5). In T2DM, atherosclerosis plays an

Cardiovascular effects and mechanisms of sodium‐glucose cotransporter‐2 inhibitors

“… 59 The weight loss occurs rapidly at first and then slows down until it reaches a plateau. 60 , 61 , 62 The initial rapid loss is considered to be the result of osmotic diuresis, while the subsequent slow loss may be the result of urinary glucose excretion causing a decrease in visceral fat mass. 63 , 64 There is evidence that obesity is an important risk factor for heart failure, but it is still controversial whether weight loss affects the outcome of patients with diabetes with significant heart failure.…”

Empagliflozin Protects Atherosclerosis Progression by Modulating Lipid Profiles and Sympathetic Activity

“…The duration of our experiment was 12 weeks, and the experimental group was treated with SGLT2 inhibitors since the 7th week. Combining previous studies, we found that SGLT2 inhibitors may inhibit in ammatory mediators with a duration of at least 8 weeks [9,10,15,27]. Therefore, we speculated that short-term of empagli ozin treatment was not enough to play an anti-in ammation effect.…”

“…In recent years, some mechanisms underlying the bene cial effect of SGLT2 inhibitor on cardiovascular diseases have been proposed. The decreased toxicity of glucose to endothelial cells may be a potential mechanism in preventing diabetic ApoE-/-mice atherosclerosis [27]. And dapagli ozin could improve the differentiation of epicardial adipose tissue and perivascular adipose tissue [28].…”

Empagliflozin protects against atherosclerosis progression by modulating lipid profiles and sympathetic activity

“…The duration in the experiment was 12 weeks, and the experimental group was treated with SGLT2i beginning at the 7th week. Combining previous studies, SGLT2i may inhibit inflammatory mediators with a duration of at least 8 weeks [8,9,44,49]. Therefore, short-term empagliflozin treatment may not be enough to have an anti-inflammatory effect.…”

“…In diabetic states, SGLT2 inhibitions might enhance glycemic control and lipoprotein clearance [21] while lowering sympathetic activation [50]. The decreased toxicity of glucose to endothelial cells may be a potential mechanism involved in the prevention of atherosclerosis in diabetic ApoE-/-mice [49]. While in non-diabetic conditions, SGLT2 inhibitors could increase adiponectin levels and reduce fat deposition [20].…”