title: Exacerbation of endothelial dysfunction during the progression of diabetes: role of oxidative stress.
abstract: To test the deterioration of endothelial function during the progression of diabetes, shear stress-induced dilation (SSID; 10, 20, and 40 dyn/cm(2)) was determined in isolated mesenteric arteries (80-120 μm in diameter) of 6-wk (6W), 3-mo (3M), and 9-mo (9M)-old male db/db mice and their wild-type (WT) controls. Nitric oxide (NO)-mediated SSID was comparable in 6W WT and db/db mice, but the dilation was significantly reduced in 3M db/db mice and declined further in 9M db/db mice. Vascular superoxide production was progressively increased in 3M and 9M db/db mice, associated with an increased expression of NADPH oxidase. Inhibition of NADPH oxidase significantly improved NO-mediated SSID in arteries of 3M, but not in 9M, db/db mice. Although endothelial nitric oxide synthase (eNOS) expression was comparable in all groups, a progressive reduction in shear stress-induced eNOS phosphorylation existed in vessels of 3M and 9M db/db mice. Moreover, inducible NOS (iNOS) that was not detected in WT, nor in 6W and 3M db/db mice, was expressed in vessels of 9M db/db mice. A significantly increased expression of nitrotyrosine in total protein and immunoprecipitated eNOS was also found in vessels of 9M db/db mice. Thus, impaired NO bioavailability plays an essential role in the endothelial dysfunction of diabetic mice, which becomes aggravated when endothelial nitrosative stress is further activated via perhaps, an additional iNOS-mediated pathway during the progression of diabetes.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York, USA.
authors.forename: An
authors.initials: A
authors.lastname: Huang
authors.forename: Yang-Ming
authors.initials: YM
authors.lastname: Yang
authors.forename: Attila
authors.initials: A
authors.lastname: Feher
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bagi
authors.forename: Gabor
authors.initials: G
authors.lastname: Kaley
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology*; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology; D006946:Hyperinsulinism / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D013481:Superoxides; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III