title: Asymmetrical dimethylarginine regulates endothelial function in methionine-induced but not in chronic homocystinemia in humans: effect of oxidative stress and proinflammatory cytokines.
abstract: BACKGROUND
  Homocystinemia is a metabolic abnormality associated with endothelial dysfunction and increased cardiovascular disease risk. The underlying mechanisms of these effects, however, are obscure.
  
  
  OBJECTIVE
  We examined the effect of asymmetrical dimethylarginine (ADMA) on endothelial dysfunction in methionine-induced and chronic homocystinemia and evaluated the regulatory role of oxidative stress and proinflammatory cytokines on the release of ADMA.
  
  
  METHODS
  In this double-blind, placebo-controlled parallel group study, 30 subjects of both sexes (15 with homocystinemia and 15 healthy controls) underwent methionine loading, with simultaneous administration of a combination of vitamin C (2 g) plus alpha-tocopherol (800 IU) or placebo. Endothelial function in forearm resistance vessels and concentrations of ADMA, oxidized LDL, and proinflammatory cytokines were determined at baseline and 4 h after methionine loading.
  
  
  RESULTS
  Both chronic and methionine-induced homocystinemia were associated with increased oxidized LDL (P < 0.01), higher expression of the proinflammatory cytokine interleukin 6 (P < 0.05), and endothelial dysfunction (P < 0.01). Although ADMA rapidly increased in acute homocystinemia (P < 0.01) and was correlated with forearm hyperemic response at 4 h after methionine loading (r = -0.722, P = 0.0001), it was not higher in subjects with high versus low fasting homocysteine. High-dose antioxidant treatment prevented methionine-induced elevation of oxidized LDL and interleukin 6 but failed to prevent the increase in ADMA or endothelial dysfunction.
  
  
  CONCLUSIONS
  Both chronic and methionine-induced homocystinemia are characterized by increased oxidative stress and proinflammatory cytokines, which may contribute to the development of endothelial dysfunction. However, the ADMA pathway is activated only in acute homocystinemia by mechanisms not mediated by oxidized LDL or proinflammatory stimuli.
authors.affiliation: Athens University Medical School, 1st Cardiology Department, Hippokration Hospital, Athens, Greece.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Antoniades
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tousoulis
authors.forename: Kyriakoula
authors.initials: K
authors.lastname: Marinou
authors.forename: Carmen
authors.initials: C
authors.lastname: Vasiliadou
authors.forename: Costantinos
authors.initials: C
authors.lastname: Tentolouris
authors.forename: George
authors.initials: G
authors.lastname: Bouras
authors.forename: Christos
authors.initials: C
authors.lastname: Pitsavos
authors.forename: Christodoulos
authors.initials: C
authors.lastname: Stefanadis
mesh_terms: D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001205:Ascorbic Acid / Q000008:administration & dosage; D008078:Cholesterol, LDL / Q000097:blood; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood* / Q000187:drug effects; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008715:Methionine / Q000009:adverse effects*; D018384:Oxidative Stress; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D024502:alpha-Tocopherol / Q000008:administration & dosage; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D008078:Cholesterol, LDL; D016207:Cytokines; D015850:Interleukin-6; C487735:dimethylarginine; D014841:von Willebrand Factor; D006710:Homocysteine; D001120:Arginine; D008715:Methionine; D024502:alpha-Tocopherol; D001205:Ascorbic Acid