title: Nɛ-homocysteinyl-lysine isopeptide is associated with progression of peripheral artery disease in patients treated with folic acid.
abstract: OBJECTIVE
  Folic acid (FA) administration can reduce plasma total homocysteine (tHcy); however, it fails to decrease cardiovascular events and progression of peripheral artery disease (PAD). Nɛ-homocysteinyl-lysine isopeptide (Nɛ-Hcy-Lys) is formed during catabolism of homocysteinylated proteins. We sought to investigate factors that determine the presence of Nɛ-Hcy-Lys in PAD patients with hyperhomocysteinemia receiving FA.
  
  
  METHODS
  We studied 131 consecutive PAD patients with tHcy > 15 μmol l(-1) taking FA 0.4 mg d(-1) for 12 months. Serum Nɛ-Hcy-Lys was determined by high-performance liquid chromatography (HPLC). We also measured interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), asymmetric dimethylarginine (ADMA) and 8-iso-prostaglandin F(2α) (8-iso-PGF(2α)).
  
  
  RESULTS
  FA administration resulted in a 70.5% decrease in tHcy (p < 0.0001). However, serum Nɛ-Hcy-Lys was detectable in 28 (21.4%) patients on FA who were more frequently current smokers and survivors of ischaemic stroke (p < 0.001). They had higher tHcy by 46.0%, PAI-1 by 51.7%, 8-iso-PGF(2α) by 59.1% and ADMA by 26.4% (all, p < 0.0001). The presence of Nɛ-Hcy-Lys was associated with lower ankle-brachial index (ABI) values (p < 0.001) and higher prevalence of cardiovascular events (p < 0.001) following therapy.
  
  
  CONCLUSIONS
  The presence of Nɛ-Hcy-Lys in one-fifth of hyperhomocysteinemic individuals with PAD despite FA treatment is associated with progression of PAD and with increased ADMA formation, oxidative stress and hypofibrinolysis.
authors.affiliation: Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: P
authors.initials: P
authors.lastname: Mazur
authors.forename: A
authors.initials: A
authors.lastname: Kozynacka
authors.forename: L
authors.initials: L
authors.lastname: Durajski
authors.forename: R
authors.initials: R
authors.lastname: Głowacki
authors.forename: R
authors.initials: R
authors.lastname: Pfitzner
authors.forename: K
authors.initials: K
authors.lastname: Fijorek
authors.forename: J
authors.initials: J
authors.lastname: Sadowski
authors.forename: A
authors.initials: A
authors.lastname: Undas
mesh_terms: D000368:Aged; D018450:Disease Progression; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008660:Metabolism; D008875:Middle Aged; D018384:Oxidative Stress; D010455:Peptides / Q000097:blood / Q000378:metabolism*; D058729:Peripheral Arterial Disease / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D011506:Proteins / Q000378:metabolism*; D014803:Vitamin B Complex / Q000008:administration & dosage*
chemical_list: D010455:Peptides; D011506:Proteins; D006710:Homocysteine; D014803:Vitamin B Complex; D005492:Folic Acid