並列タイトル等カナグリフロジンは、ApoE欠損マウスの糖尿病誘発性血管機能障害を予防する
Canagliflozin and Vascular Function
タイトル（掲載誌）Journal of Atherosclerosis and Thrombosis
一般注記Aim: 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 eNOSSer1177 and Akt but increased the phosphorylation of eNOSThr495 and p38 MAPK in HUVECs.Conclusion: Canagliflozin prevents endothelial dysfunction and atherogenesis in diabetic ApoE－/－ mice. Anti-inflammatory and antioxidative potential due to reduced glucose toxicity to endothelial cells might be its underlying mechanisms.
DOIinfo:doi/10.5551/jat.52100
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