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
Rationale: Ceruloplasmin (Cp) antioxidant function is mainly related to its Ferroxidase I (FeOxI) activity, which influences iron-dependent oxidative and nitrosative radical species generation. Peroxynitrite (ONOO-), whose production is increased in heart failure (HF), can affect Cp antioxidant function through aminoacid modification.
Objective: We investigated the relationship between FeOxI and Cp tyrosine and cysteine modification and explored in a cohort of HF patients the potential clinical relevance of serum FeOxI.
Methods and Results: In chronic HF patients (n=96, 76+9 years, NYHA class2.9+0.8), and age-matched controls (n=35,CTR) serum FeOxI, FeOxII, Cp, nitrotyrosine-bound Cp, BNP, norepinephrine, and hsCRP were measured and the patients were followed-up for 24 months. Cp, BNP, norepinephrine and hsCRP were increased in HF vs CTR. FeOxI was decreased in HF (-20%) and inversely related to nitrotyrosine-bound Cp (r= - 0.305,P=0.003). In HF, FeOxI lower tertile had a mortality rate doubled compared to middle-higher tertiles. FeOxI emerged as a mortality predictor (HR 2.95, CI 1.29-6.75, P=0.011) after adjustment for age, sex, hypertension, smoking, sodium level, eGFR and hsCRP. In experimental settings, ONOO- incubation of serum samples and isolated purified Cp reduced FeOxI activity while increasing Cp tyrosine nitration and cysteine thiol oxidation. Reduced glutathione prevented ONOO-induced FeOxI drop, tyrosine nitration and cysteine oxidation; flavonoid(-)-epicatechin, which prevented Cp tyrosine nitration but not cysteine oxidation, partially impeded ONOO-induced FeOxI drop.
Conclusions: Reduced activity of serum FeOxI is associated with Cp nitration and reduced survival in HF patients. Both Cp tyrosine nitration and cysteine thiol oxidation may be operant in vivo in ONOO-induced FeOxI activity inhibition.
- Ferroxidase I Activity
- Nitrosative stress
- heart failure
- oxidative stress
- Received October 13, 2013.
- Revision received March 16, 2014.
- Accepted March 31, 2014.