title: NOX2 up-regulation is associated with artery dysfunction in patients with peripheral artery disease.
abstract: OBJECTIVE
  Oxidative stress seems to play a role in impairing flow-mediated dilation (FMD) in patients with peripheral artery disease (PAD) but the underlying mechanism is still undefined. We evaluated whether NOX2, the catalytic core of NADPH oxidase, the most important producer of reactive oxidant species (ROS), is implicated in impairing FMD.
  
  
  METHODS
  We measured FMD, urinary isoprostanes, a marker of oxidative stress, nitric oxide generation by serum levels of nitrite/nitrate (NOx), and serum levels of soluble NOX2-derived peptide (sNOX2-dp), a marker of NOX2 activation, in 50 PAD patients and 50 controls. Also, we performed an interventional cross-over study to assess if propionyl-L-carnitine (PLC) (6g/day), vs. placebo, was able to affect FMD via an oxidative stress-mediated mechanism.
  
  
  RESULTS
  Compared to controls, patients with PAD had enhanced sNOX2-dp and isoprostanes and reduced NOx and FMD. Multiple linear regression analysis showed that FMD was independently associated with sNOX2-dp. After PLC infusion FMD increased while sNOX2-dp and isoprostanes significantly decreased; no changes were observed after placebo. In vitro study by incubating platelets or white cells with PLC demonstrated a significant inhibition of p47(phox) translocation on cellular surface and ROS generated by NOX2 activation.
  
  
  CONCLUSIONS
  This study suggests that in PAD patients ROS generated by NOX2 contribute to reduce FMD and that the administration of an antioxidant is able to improve arterial dilatation via NOX2 inhibition.
authors.affiliation: I Clinica Medica, Sapienza University, Rome, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Loffredo
authors.forename: Roberto
authors.initials: R
authors.lastname: Carnevale
authors.forename: Roberto
authors.initials: R
authors.lastname: Cangemi
authors.forename: Francesco
authors.initials: F
authors.lastname: Angelico
authors.forename: Teresa
authors.initials: T
authors.lastname: Augelletti
authors.forename: Serena
authors.initials: S
authors.lastname: Di Santo
authors.forename: Cinzia M
authors.initials: CM
authors.lastname: Calabrese
authors.forename: Luigi
authors.initials: L
authors.lastname: Della Volpe
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pignatelli
authors.forename: Ludovica
authors.initials: L
authors.lastname: Perri
authors.forename: Stefania
authors.initials: S
authors.lastname: Basili
authors.forename: Francesco
authors.initials: F
authors.lastname: Violi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D008875:Middle Aged; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000096:biosynthesis*; D058729:Peripheral Arterial Disease / Q000201:enzymology* / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology
chemical_list: D015415:Biomarkers; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases