title: Low serum ferroxidase I activity is associated with mortality in heart failure and related to both peroxynitrite-induced cysteine oxidation and tyrosine nitration of ceruloplasmin.
abstract: BACKGROUND
  Ceruloplasmin antioxidant function is mainly related to its ferroxidase I (FeOxI) activity, which influences iron-dependent oxidative and nitrosative radical species generation. Peroxynitrite, whose production is increased in heart failure (HF), can affect ceruloplasmin antioxidant function through amino acid modification.
  
  
  OBJECTIVE
  We investigated the relationship between FeOxI and ceruloplasmin tyrosine and cysteine modification and explored in a cohort of patients with HF the potential clinical relevance of serum FeOxI.
  
  
  RESULTS
  In patients with chronic HF (n=96, 76 ± 9 years; New York Heart Association class, 2.9 ± 0.8) and age-matched controls (n=35), serum FeOxI, FeOxII, ceruloplasmin, nitrotyrosine-bound ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were measured, and the patients were followed up for 24 months. Ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were increased in HF versus controls. FeOxI was decreased in HF (-20%) and inversely related to nitrotyrosine-bound ceruloplasmin (r, -0.305; P=0.003). In HF, FeOxI lower tertile had a mortality rate doubled compared with middle-higher tertiles. FeOxI emerged as a mortality predictor (hazard ratio, 2.95; 95% confidence intervals [1.29-6.75]; P=0.011) after adjustment for age, sex, hypertension, smoking, sodium level, estimated glomerular filtration rate, and high-sensitivity C-reactive protein. In experimental settings, peroxynitrite incubation of serum samples and isolated purified ceruloplasmin reduced FeOxI activity while increasing ceruloplasmin tyrosine nitration and cysteine thiol oxidation. Reduced glutathione prevented peroxynitrite-induced FeOxI drop, tyrosine nitration, and cysteine oxidation; flavonoid(-)-epicatechin, which prevented ceruloplasmin tyrosine nitration but not cysteine oxidation, partially impeded peroxynitrite-induced FeOxI drop.
  
  
  CONCLUSIONS
  Reduced activity of serum FeOxI is associated with ceruloplasmin nitration and reduced survival in patients with HF. Both ceruloplasmin tyrosine nitration and cysteine thiol oxidation may be operant in vivo in peroxynitrite-induced FeOxI activity inhibition.
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.). aderville.cabassi@unipr.it.
authors.forename: Aderville
authors.initials: A
authors.lastname: Cabassi
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Simone Maurizio
authors.initials: SM
authors.lastname: Binno
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Stefano
authors.initials: S
authors.lastname: Tedeschi
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Valerie
authors.initials: V
authors.lastname: Ruzicka
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Simona
authors.initials: S
authors.lastname: Dancelli
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Rossana
authors.initials: R
authors.lastname: Rocco
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Vanni
authors.initials: V
authors.lastname: Vicini
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Pietro
authors.initials: P
authors.lastname: Coghi
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Regolisti
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Alberto
authors.initials: A
authors.lastname: Montanari
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Enrico
authors.initials: E
authors.lastname: Fiaccadori
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Paolo
authors.initials: P
authors.lastname: Govoni
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Massimo
authors.initials: M
authors.lastname: Piepoli
authors.affiliation: From the Cardiorenal Research Unit (A.C., S.M.B., S.T., V.R., S.D., R.R., P.C., G.R., A.M., E.F.), Laboratory of Experimental Physiopathology (A.C., V.R., S.D., P.C., A.M.), and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; Histology and Embriology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma Medical School, Parma, Italy (P.G.); Cardiology Clinic, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy (V.V.); Cardiology Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy (M.P.); and Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada (J.d.C.).
authors.forename: Jacques
authors.initials: J
authors.lastname: de Champlain
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D002570:Ceruloplasmin / Q000378:metabolism*; D015331:Cohort Studies; D003545:Cysteine / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality*; D006801:Humans; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D015996:Survival Rate; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D020097:Natriuretic Peptide, Brain; D030421:Peroxynitrous Acid; D014443:Tyrosine; D002097:C-Reactive Protein; D002570:Ceruloplasmin; D003545:Cysteine; D009638:Norepinephrine
keywords: ceruloplasmin; heart failure; mortality; oxidative stress