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ID 115926
タイトル別表記
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 徳島大学大学院医科学教育部(医学専攻)
Salim, Hotimah Masdan Tokushima University
キーワード
SGLT2 inhibitor
Canagliflozin
Atherosclerosis
Endothelial dysfunction
資料タイプ
学位論文
抄録
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.
掲載誌名
Journal of Atherosclerosis and Thrombosis
ISSN
18803873
13403478
出版者
Japan Atherosclerosis Society
27
11
開始ページ
1141
終了ページ
1151
発行日
2020-11-01
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Arief Rahadianの学位論文として提出され,学位審査・授与の対象となっている。
権利情報
This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.(https://creativecommons.org/licenses/by-nc-sa/4.0/)
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3494号
学位記番号
甲医第1476号
学位授与年月日
2021-03-23
学位名
博士(医学)
学位授与機関
徳島大学
部局
医学系
病院