title: Proteolytic and genetic variation of the alpha-2-antiplasmin C-terminus in myocardial infarction.
abstract: Alpha-2-antiplasmin (α2AP) undergoes both N- and C-terminal cleavages, which significantly modify its activities. Compared with other Ser protease inhibitors (serpins), α2AP contains an ~50-residue-extended C-terminus, which binds plasmin(ogen). We developed 2 new ELISAs to measure the antigen levels of free total α2AP and free C-terminally intact α2AP to investigate whether α2AP antigen levels or α2AP C-terminal cleavage were associated with myocardial infarction (MI) in 320 male MI survivors and 169 age-matched controls. Patients had 15.2% reduced total α2AP antigen levels compared with controls (93.8 vs 110.6 U/dL, P < .001), with a 10.1-fold (95% confidence interval [CI]: 5.5-18.9) increased MI risk for levels in the 1st quartile compared with the 4th quartile. The percentage of C-terminal cleavage did not differ between patients and controls (38.7% and 38.1%, respectively, P = .44). In addition, all individuals were genotyped for the polymorphism Arg407Lys, which is located near the start of the extended C-terminus. Arg407Lys was not associated with α2AP C-terminal cleavage, total α2AP antigen levels, or MI risk (odds ratios compared with Arg/Arg: Arg/Lys 0.74, 95% CI: 0.50-1.10; Lys/Lys 0.77, 95% CI: 0.31-1.92). Our data show that levels of free full-length α2AP were decreased in MI, that the percentage of C-terminally cleaved α2AP was unaltered, and that Arg407Lys did not influence α2AP levels or MI risk.
authors.affiliation: Division of Cardiovascular & Diabetes Research, Section on Mechanisms of Thrombosis, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
authors.forename: Shirley
authors.initials: S
authors.lastname: Uitte de Willige
authors.forename: Megan
authors.initials: M
authors.lastname: Miedzak
authors.forename: Angela M
authors.initials: AM
authors.lastname: Carter
authors.forename: Ton
authors.initials: T
authors.lastname: Lisman
authors.forename: Frits R
authors.initials: FR
authors.lastname: Rosendaal
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Grant
authors.forename: Helen
authors.initials: H
authors.lastname: Philippou
authors.forename: Robert A S
authors.initials: RA
authors.lastname: Ariëns
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D001120:Arginine / Q000235:genetics; D016022:Case-Control Studies; D005838:Genotype; D006801:Humans; D008239:Lysine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000502:physiology; D009203:Myocardial Infarction / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D054928:Validation Studies as Topic; D000979:alpha-2-Antiplasmin / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000979:alpha-2-Antiplasmin; D001120:Arginine; D008239:Lysine