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Glucose‐lowering agent and AGE inhibitor restores eNOS function in diabetes
Author(s) -
Oak JeongHo,
Cai Hua “Linda”
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1162-c
Subject(s) - enos , medicine , endocrinology , tetrahydrobiopterin , metformin , ramipril , diabetes mellitus , nitric oxide , endothelial dysfunction , nitric oxide synthase , chemistry , blood pressure
Endothelial dysfunction characterized by a loss of nitric oxide (NO) is associated with diabetic vascular diseases. We sought to examine impact of diabetes, glucose‐lowering and advanced glycation end product (AGE) antagonism on eNOS function. Male C57BL6 mice (6–8 wks old) were injected with streptozocin (100 mg/kg/day) via tail vein for 3 days. Blood glucose levels in control and STZ‐treated mice were 148 ±3 vs 452 ±15 mg/dl respectively. Since day 4, diabetic mice were injected with oral glucose lowering drug Metformin (100 mg/kg/day) or AGE antagonist Aminoguanidine (100 mg/kg/day) for 3 days. Diabetic mice had markedly increased aortic hydrogen peroxide production which was significantly attenuated by L‐NAME. Tetrahydrobiopterin levels, bioavailable NO detected using electron spin resonance (ESR) technology, and endothelium‐dependent vasorelaxation were all markedly reduced in diabetic aortas. We have recently shown that deficiency in endothelial dihydrofolate reductase (DHFR) causes tetrahydrobiopterin deficiency and uncoupling of eNOS (PNAS, 2005). Indeed, aortic expression of DHFR was significantly downregulated in diabetic mice. Metformin or Aminoguanidine restored expression of DHFR although neither significantly decreased blood glucose levels. Either agent also modestly upregulated eNOS expression and thus improved DHFR/eNOS ratio. Metformin or Amigoguanidine also diminished L‐NAME sensitive superoxide and hydrogen peroxide production in diabetic aortas. In conclusion, data from the present study seem to suggest that glucose‐lowering or AGE antagonism is beneficial for diabetic patients by directly improving endothelial function via restoration of eNOS function. This work is supported by American Heart Association and American Diabetes Association Grants 0435189N and 7‐04‐RA‐16, and NIH Grants HL077440 and HL081571 (all to H Cai).