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

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書誌事項

タイトル
Canagliflozin Prevents Diabetes-Induced Vascular Dysfunction in ApoE-Deficient Mice
タイトル別名
  • 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
著者
ラハディアン, アリエフ
著者別名
  • Rahadian, Arief
著者
福田, 大受
著者別名
  • フクダ, ダイジュ
  • Fukuda, Daiju
著者
Salim, Hotimah Masdan
著者
八木, 秀介
著者別名
  • ヤギ, シュウスケ
  • Yagi, Shusuke
著者
楠瀬, 賢也
著者別名
  • クスノセ, ケンヤ
  • Kusunose, Kenya
著者
山田, 博胤
著者別名
  • ヤマダ, ヒロツグ
  • Yamada, Hirotsugu
著者
添木, 武
著者別名
  • ソエキ, タケシ
  • Soeki, Takeshi
著者
佐田, 政隆
著者別名
  • サタ, マサタカ
  • Sata, Masataka
学位授与大学
徳島大学
取得学位
博士（医学）
学位授与番号
甲医第1476号
学位授与年月日
2021-03-23

説明

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.

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