title: NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis.
abstract: BACKGROUND
  In diabetes mellitus, vascular complications such as atherosclerosis are a major cause of death. The key underlying pathomechanisms are unclear. However, hyperglycemic oxidative stress derived from NADPH oxidase (Nox), the only known dedicated enzyme to generate reactive oxygen species appears to play a role. Here we identify the Nox1 isoform as playing a key and pharmacologically targetable role in the accelerated development of diabetic atherosclerosis.
  
  
  RESULTS
  Human aortic endothelial cells exposed to hyperglycemic conditions showed increased expression of Nox1, oxidative stress, and proinflammatory markers in a Nox1-siRNA reversible manner. Similarly, the specific Nox inhibitor, GKT137831, prevented oxidative stress in response to hyperglycemia in human aortic endothelial cells. To examine these observations in vivo, we investigated the role of Nox1 on plaque development in apolipoprotein E-deficient mice 10 weeks after induction of diabetes mellitus. Deletion of Nox1, but not Nox4, had a profound antiatherosclerotic effect correlating with reduced reactive oxygen species formation, attenuation of chemokine expression, vascular adhesion of leukocytes, macrophage infiltration, and reduced expression of proinflammatory and profibrotic markers. Similarly, treatment of diabetic apolipoprotein E-deficient mice with GKT137831 attenuated atherosclerosis development.
  
  
  CONCLUSIONS
  These studies identify a major pathological role for Nox1 and suggest that Nox1-dependent oxidative stress is a promising target for diabetic vasculopathies, including atherosclerosis.
authors.affiliation: Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, Melbourne, VIctoria 8008, Australia.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Gray
authors.forename: Elyse
authors.initials: E
authors.lastname: Di Marco
authors.forename: Jun
authors.initials: J
authors.lastname: Okabe
authors.forename: Cedric
authors.initials: C
authors.lastname: Szyndralewiez
authors.forename: Freddy
authors.initials: F
authors.lastname: Heitz
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Montezano
authors.forename: Judy B
authors.initials: JB
authors.lastname: de Haan
authors.forename: Christine
authors.initials: C
authors.lastname: Koulis
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.forename: Karen L
authors.initials: KL
authors.lastname: Andrews
authors.forename: Jaye P F
authors.initials: JP
authors.lastname: Chin-Dusting
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.forename: Kirstin
authors.initials: K
authors.lastname: Wingler
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Harald H H W
authors.initials: HH
authors.lastname: Schmidt
authors.forename: Karin A
authors.initials: KA
authors.lastname: Jandeleit-Dahm
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009247:NADH, NADPH Oxidoreductases / Q000502:physiology*; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000502:physiology*; D009924:Organ Culture Techniques; D020033:Protein Isoforms / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C000614711:NOX1 protein, mouse
keywords: NADPH oxidase; atherosclerosis; diabetes mellitus; oxidative stress