Rahadian, Arief and Fukuda, Daiju and Salim, Hotimah Masdan and Yagi, Shusuke and Kusunose, Kenya and Yamada, Hirotsugu (2020) Canagliflozin Prevents Diabetes-Induced Vascular Dysfunction in ApoE-Deficient Mice. Journal of Atherosclerosis and Thrombosis, 27 (11). pp. 1141-1151.
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Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Atherosclerosis; Canagliflozin; Endothelial dysfunction; SGLT2 inhibitor |
| Subjects: | R Medicine > RC Internal medicine > RC581-951 Specialties of internal medicine |
| Divisions: | Faculty of Medicine > Program Study of Medicine |
| Depositing User: | Mr. . Aji |
| Date Deposited: | 12 Dec 2022 05:21 |
| Last Modified: | 12 Dec 2022 05:21 |
| URI: | http://repository.unusa.ac.id/id/eprint/9091 |
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