title: Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis.
abstract: We explored the role of asymmetrical dimethylarginine (ADMA) as a cause of endothelial dysfunction induced by systemic inflammation. In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli, but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans. In study 1 we recruited 351 patients with coronary artery disease (CAD) and 87 healthy controls. In study 2 we recruited 69 CAD, 69 healthy, and 10 patients with rheumatoid arthritis, whereas in study 3, 22 healthy and 70 CAD subjects were randomly assigned to Salmonella typhii vaccination (n=11 healthy and n=60 CAD) or placebo (n=11 healthy and n=10 CAD). Circulating interleukin 6/ADMA and flow-mediated dilation (FMD) were measured at 0 and 8 hours. In study 1, ADMA was inversely correlated with FMD in healthy individuals and CAD patients (P<0.0001 for both). However, interleukin 6 was inversely correlated with FMD (P<0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (r=0.515; P<0.0001) compared with CAD (r=0.289; P=0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (P<0.0001) and ADMA (P=0.004) but lower FMD (P=0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (P<0.001) and CAD (P<0.001) subjects. FMD was reduced in healthy subjects (P<0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (P<0.001). Systemic, low-grade inflammation leads to increased ADMA that may induce endothelial dysfunction. This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans.
authors.affiliation: 1st Cardiology Department, Athens University Medical School, Ileias 8, Gerakas Attikis 153 44, Athens, Greece. antoniades@vodafone.net.gr
authors.forename: Charalambos
authors.initials: C
authors.lastname: Antoniades
authors.forename: Michael
authors.initials: M
authors.lastname: Demosthenous
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tousoulis
authors.forename: Alexios S
authors.initials: AS
authors.lastname: Antonopoulos
authors.forename: Charalambos
authors.initials: C
authors.lastname: Vlachopoulos
authors.forename: Marina
authors.initials: M
authors.lastname: Toutouza
authors.forename: Kyriakoula
authors.initials: K
authors.lastname: Marinou
authors.forename: Constantinos
authors.initials: C
authors.lastname: Bakogiannis
authors.forename: Kleio
authors.initials: K
authors.lastname: Mavragani
authors.forename: George
authors.initials: G
authors.lastname: Lazaros
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Koumallos
authors.forename: Costas
authors.initials: C
authors.lastname: Triantafyllou
authors.forename: Dimitris
authors.initials: D
authors.lastname: Lymperiadis
authors.forename: Michael
authors.initials: M
authors.lastname: Koutsilieris
authors.forename: Christodoulos
authors.initials: C
authors.lastname: Stefanadis
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D003324:Coronary Artery Disease / Q000097:blood / Q000209:etiology / Q000503:physiopathology; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D008297:Male; D010865:Pilot Projects; D011379:Prognosis; D014664:Vasodilation / Q000502:physiology*
chemical_list: C487735:dimethylarginine; D001120:Arginine