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ID 115926
Title Alternative
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
Author
Rahadian, Arief Tokushima University
Salim, Hotimah Masdan Tokushima University
Keywords
SGLT2 inhibitor
Canagliflozin
Atherosclerosis
Endothelial dysfunction
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Journal of Atherosclerosis and Thrombosis
ISSN
18803873
13403478
Publisher
Japan Atherosclerosis Society
Volume
27
Issue
11
Start Page
1141
End Page
1151
Published Date
2020-11-01
Remark
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。
Rights
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
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3494号
Diploma Number
甲医第1476号
Granted Date
2021-03-23
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences
University Hospital