Canagliflozin and Vascular Function
Rahadian, Arief Tokushima University
Fukuda, Daiju Tokushima University KAKEN Search Researchers
Salim, Hotimah Masdan Tokushima University
Yagi, Shusuke Tokushima University KAKEN Search Researchers
Kusunose, Kenya Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Yamada, Hirotsugu Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Soeki, Takeshi Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Sata, Masataka Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Thesis or Dissertation
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 of Atherosclerosis and Thrombosis
Japan Atherosclerosis Society
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k3494_abstract_review.pdf 197 KB
k3494_fulltext.pdf 879 KB
|MEXT report number||
Doctor of Medical Science