Glycemic Control with Ipragliflozin, a Novel Selective SGLT2 Inhibitor, Ameliorated Endothelial Dysfunction in Streptozotocin-Induced Diabetic Mouse

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 C57BL/6 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 eNOSSer1177 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 eNOSSer1177 (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.

[1]  M. Delgado-Rodríguez,et al.  Systematic review and meta-analysis. , 2017, Medicina intensiva.

[2]  V. Perkovic,et al.  Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. , 2016, The lancet. Diabetes & endocrinology.

[3]  Y. Higashikuni,et al.  Dipeptidyl peptidase-4 inhibitor, linagliptin, ameliorates endothelial dysfunction and atherogenesis in normoglycemic apolipoprotein-E deficient mice. , 2016, Vascular pharmacology.

[4]  M. Fischereder,et al.  Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. , 2016, The New England journal of medicine.

[5]  T. Hirano,et al.  Amelioration of Hyperglycemia with a Sodium-Glucose Cotransporter 2 Inhibitor Prevents Macrophage-Driven Atherosclerosis through Macrophage Foam Cell Formation Suppression in Type 1 and Type 2 Diabetic Mice , 2015, PloS one.

[6]  T. Ohkura Ipragliflozin: A novel sodium-glucose cotransporter 2 inhibitor developed in Japan. , 2015, World journal of diabetes.

[7]  T. Münzel,et al.  The Sodium-Glucose Co-Transporter 2 Inhibitor Empagliflozin Improves Diabetes-Induced Vascular Dysfunction in the Streptozotocin Diabetes Rat Model by Interfering with Oxidative Stress and Glucotoxicity , 2014, PloS one.

[8]  Yu Hasegawa,et al.  Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice , 2014, Cardiovascular Diabetology.

[9]  S. Mudaliar,et al.  Exploring the Potential of the SGLT2 Inhibitor Dapagliflozin in Type 1 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Pilot Study , 2014, Diabetes Care.

[10]  M. Sata,et al.  Azilsartan, an angiotensin II type 1 receptor blocker, restores endothelial function by reducing vascular inflammation and by increasing the phosphorylation ratio Ser1177/Thr497 of endothelial nitric oxide synthase in diabetic mice , 2014, Cardiovascular Diabetology.

[11]  H. Koepsell,et al.  Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. , 2014, American journal of physiology. Renal physiology.

[12]  S. Mudaliar,et al.  Exploring the Potential of the SGLT 2 Inhibitor Dapagli fl ozin in Type 1 Diabetes : A Randomized , Double-Blind , Placebo-Controlled Pilot Study , 2014 .

[13]  M. Sasamata,et al.  Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice. , 2013, European journal of pharmacology.

[14]  E. Ferrannini,et al.  Active- and placebo-controlled dose-finding study to assess the efficacy, safety, and tolerability of multiple doses of ipragliflozin in patients with type 2 diabetes mellitus. , 2013, Journal of diabetes and its complications.

[15]  S. Yamagishi,et al.  Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression. , 2013, The American journal of pathology.

[16]  Dhiren P. Shah,et al.  ON OXIDATIVE STRESS AND DIABETIC COMPLICATIONS , 2013 .

[17]  S. Schwartz,et al.  Safety, pharmacokinetic, and pharmacodynamic profiles of ipragliflozin (ASP1941), a novel and selective inhibitor of sodium-dependent glucose co-transporter 2, in patients with type 2 diabetes mellitus. , 2011, Diabetes technology & therapeutics.

[18]  T. Münzel,et al.  Vascular Dysfunction in Experimental Diabetes Is Improved by Pentaerithrityl Tetranitrate but Not Isosorbide-5-Mononitrate Therapy , 2011, Diabetes.

[19]  B. Hering,et al.  The streptozotocin-induced diabetic nude mouse model: differences between animals from different sources. , 2011, Comparative medicine.

[20]  C. Corsso,et al.  Cell therapy in dilated cardiomyopathy: from animal models to clinical trials. , 2011 .

[21]  T. Münzel,et al.  Vascular Dysfunction in Streptozotocin-Induced Experimental Diabetes Strictly Depends on Insulin Deficiency , 2011, Journal of Vascular Research.

[22]  R. Henry,et al.  SGLT2 inhibition — a novel strategy for diabetes treatment , 2010, Nature Reviews Drug Discovery.

[23]  N. Calcutt,et al.  Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials , 2009, Nature Reviews Drug Discovery.

[24]  T. Imaizumi,et al.  Receptor for advanced glycation end products (RAGE): a novel therapeutic target for diabetic vascular complication. , 2008, Current pharmaceutical design.

[25]  A. Shah,et al.  NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes. , 2006, The American journal of pathology.

[26]  A. Yoshimura,et al.  Pigment Epithelium-derived Factor Inhibits Advanced Glycation End Product-induced Retinal Vascular Hyperpermeability by Blocking Reactive Oxygen Species-mediated Vascular Endothelial Growth Factor Expression* , 2006, Journal of Biological Chemistry.

[27]  R. de Caterina,et al.  Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. , 2004, Cardiovascular research.

[28]  S. Matsumoto,et al.  Evidence for contribution of vascular NAD(P)H oxidase to increased oxidative stress in animal models of diabetes and obesity. , 2004, Free radical biology & medicine.

[29]  R. de Caterina,et al.  [Advanced glycation endproducts: implications for accelerated atherosclerosis in diabetes]. , 2004, Recenti progressi in medicina.

[30]  G. D. Johnston,et al.  Impaired endothelium-dependent and independent vasodilation in patients with Type 2 (non-insulin-dependent) diabetes mellitus , 1992, Diabetologia.

[31]  T. Münzel,et al.  Mechanisms Underlying Endothelial Dysfunction in Diabetes Mellitus , 2001, Circulation research.

[32]  M. Nawano,et al.  Improved diabetic syndrome in C57BL/KsJ‐db/db mice by oral administration of the Na+‐glucose cotransporter inhibitor T‐1095 , 2001, British journal of pharmacology.

[33]  D. Sorescu,et al.  NAD(P)H oxidase: role in cardiovascular biology and disease. , 2000, Circulation research.

[34]  M. Grant,et al.  Increased H2O2, vascular endothelial growth factor and receptors in the retina of the BBZ/Wor diabetic rat. , 2000, Free radical biology & medicine.

[35]  T. Ishiwata,et al.  Deposition of advanced glycation end products (AGE) and expression of the receptor for AGE in cardiovascular tissue of the diabetic rat. , 1998, International journal of experimental pathology.

[36]  M. Sampson,et al.  Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. , 1996, Journal of the American College of Cardiology.

[37]  M. Creager,et al.  -.____----.---_-Impaired Nitric Oxide-Mediated Vasodilation in Patients With Non-Insulin-Dependent Diabetes Mellitw , 2016 .

[38]  S. Hager,et al.  Endothelial dysfunction in a model of hyperglycemia and hyperinsulinemia. , 1995, The American journal of physiology.

[39]  M. Creager,et al.  Impaired Endothelium‐Dependent Vasodilation in Patients With Insulin‐Dependent Diabetes Mellitus , 1993, Circulation.

[40]  H. Bohlen,et al.  Topical hyperglycemia rapidly suppresses EDRF-mediated vasodilation of normal rat arterioles. , 1993, The American journal of physiology.

[41]  R. Cohen,et al.  Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. , 1990, The Journal of clinical investigation.