Journal
FRONTIERS IN CARDIOVASCULAR MEDICINE
Volume 3, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fcvm.2016.00043
Keywords
SGLT2 inhibitor; hyperglycemia; endothelial function; inflammation; oxidative stress
Categories
Funding
- JSPS Kakenhi [25460369, 24659392, 22390159, 25670390, 25293184]
- MEXT KAKENHI [21117007]
- Astellas Pharma, Inc.
- Grants-in-Aid for Scientific Research [24659392, 16K01823, 16H05299, 22390159, 25460369, 21117007, 25670390] Funding Source: KAKEN
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Background: Endothelial dysfunction caused by increased oxidative stress is a critical initiator of macro- and micro-vascular disease development in diabetic patients. Ipragliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, offers a novel approach for the treatment of diabetes by enhancing urinary glucose excretion. The aim of this study was to examine whether ipragliflozin attenuates endothelial dysfunction in diabetic mice. Methods: Eight-week-old male C57BU6 mice were treated with streptozotocin (150 mg/ kg) by a single intraperitoneal injection to induce diabetes mellitus. At 3 days of injection, ipragliflozin (3 mg/kg/day) was administered via gavage for 3 weeks. Vascular function was assessed by isometric tension recording. Human umbilical vein endothelial cells (HUVEC) were used for in vitro experiments. RNA and protein expression were examined by quantitative RT-PCR (qPCR) and western blot, respectively. Oxidative stress was determined by measuring urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) level. Results: Ipragliflozin administration significantly reduced blood glucose level (P < 0.001) and attenuated the impairment of endothelial function in diabetic mice, as determined by acetylcholine-dependent vasodilation (P < 0.001). Ipragliflozin did not alter metabolic parameters, such as body weight and food intake. Ipragliflozin administration ameliorated impaired phosphorylation of Akt and eNOS(Ser1177) in the abdominal aorta and reduced reactive oxygen species generation as determined by urinary excretion of 8-OHdG in diabetic mice. Furthermore, qPCR analyses demonstrated that ipragliflozin decreased the expression of inflammatory molecules [e.g., monocyte chemoattractant protein-1 (MCP-1) vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule (ICAM)-1] in the abdominal aorta (P < 0.05). In in vitro studies, incubation with methylglyoxal, one of the advanced glycation end products, significantly impaired phosphorylation of Akt and eNOS(Ser1177) (P < 0.01) and increased the expression of MCP-1, VCAM-1, and ICAM-1 in HUVEC. Conclusion: Ipragliflozin improved hyperglycemia and prevented the development of endothelial dysfunction under a hyperglycemic state, at least partially by attenuation of oxidative stress.
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