title: Endothelin-1 Overexpression Exaggerates Diabetes-Induced Endothelial Dysfunction by Altering Oxidative Stress.
abstract: Increased endothelin (ET)-1 expression causes endothelial dysfunction and oxidative stress. Plasma ET-1 is increased in patients with diabetes mellitus. Since endothelial dysfunction often precedes vascular complications in diabetes, we hypothesized that overexpression of ET-1 in the endothelium would exaggerate diabetes-induced endothelial dysfunction.
  
  
  
  Diabetes was induced by streptozotocin treatment (55mg/kg/day, i.p.) for 5 days in 6-week-old male wild type (WT) mice and in mice overexpressing human ET-1 restricted to the endothelium (eET-1). Mice were studied 14 weeks later. Small mesenteric artery (MA) endothelial function and vascular remodeling by pressurized myography, reactive oxygen species (ROS) production by dihydroethidium staining and mRNA expression by reverse transcription/quantitative PCR were determined.
  
  
  
  Endothelium-dependent vasodilatory responses to acetylcholine of MA were reduced 24% by diabetes in WT ( P < 0.05), and further decreased by 12% in eET-1 ( P < 0.05). Diabetes decreased MA media/lumen in WT and eET-1 ( P < 0.05), whereas ET-1 overexpression increased MA media/lumen similarly in diabetic and nondiabetic WT mice ( P < 0.05). Vascular ROS production was increased 2-fold by diabetes in WT ( P < 0.05) and further augmented 1.7-fold in eET-1 ( P < 0.05). Diabetes reduced endothelial nitric oxide synthase (eNOS, Nos3 ) expression in eET-1 by 31% ( P < 0.05) but not in WT. Induction of diabetes caused a 52% ( P < 0.05) increase in superoxide dismutase 1 ( Sod1 ) and a 32% ( P < 0.05) increase in Sod2 expression in WT but not in eET-1.
  
  
  
  Increased expression of ET-1 exaggerates diabetes-induced endothelial dysfunction. This may be caused by decrease in eNOS expression, increase in vascular oxidative stress, and decrease in antioxidant capacity.
authors.affiliation: Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research , Montréal, Québec , Canada.
authors.forename: Noureddine
authors.initials: N
authors.lastname: Idris-Khodja
authors.affiliation: Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research , Montréal, Québec , Canada.
authors.forename: Sofiane
authors.initials: S
authors.lastname: Ouerd
authors.affiliation: Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research , Montréal, Québec , Canada.
authors.forename: Muhammad Oneeb Rehman
authors.initials: MOR
authors.lastname: Mian
authors.affiliation: Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research , Montréal, Québec , Canada.
authors.forename: Jordan
authors.initials: J
authors.lastname: Gornitsky
authors.affiliation: Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research , Montréal, Québec , Canada.
authors.forename: Tlili
authors.initials: T
authors.lastname: Barhoumi
authors.affiliation: Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research , Montréal, Québec , Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.affiliation: Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research, Montréal, Québec, Canada.|Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species
chemical_list: D019332:Endothelin-1; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III