Abstract 19636: Cardioprotective Role of Ceruloplasmin in Heart Failure via Inhibition of Myeloperoxidase Activity
Elevated levels of the acute phase reactant ceruloplasmin (Cp) and the neutrophil heme protein myeloperoxidase (MPO) predict adverse clinical outcomes in the setting of acute coronary syndromes and heart failure (HF), yet whether the contribution of elevated Cp to HF is beneficial or detrimental is unclear. We tested the hypothesis that elevated Cp is cardioprotective via its ability to inhibit MPO in the following studies. Left anterior descending coronary artery ligation (LADx) was performed on wild type (WT) and Cp+/- mice. Four weeks after LADx, Cp+/- mice demonstrated greater impairment of cardiac structure and function, including increased myocardial fibrosis compared to WT (p<0.05). 24-hour urine MPO activity was increased after LADx, and is further increased in Cp+/- mice compared to WT with corresponding reduction in 24-hour urine Cp activity, thus suggesting the MPO inhibitory effects of Cp. In a series of in vitro assays examining MPO inhibitory capacity (MIC), addition of exogenous Cp (200 ug/mL, 60 min incubation) diminished MPO activity across serial dilutions of MPO (Figure 1A) while plasma from Cp+/- mice showed diminished ability (30% decrease vs WT, p<0.01) to inhibit MPO activity compared to control, suggesting that lowering Cp can affect MIC. Additionally, plasma from HF patients vs non-HF demonstrated diminished MIC in response to exogenous MPO despite higher Cp mass in plasma (Figure 1B), while Cp immunoprecipitation greatly attenuated MIC in normal human plasma (p<0.01). Utilizing an MPO antibody capture technique, we compared MPO activities in plasma samples from HF (with lower MIC) versus non-HF (with higher MIC) patients and noted higher MPO activity in patients with HF versus non-HF (p<0.01). These studies suggest a cardioprotective role for Cp in HF via modulation of MPO activity.
Author Disclosures: D.J. Kennedy: Research Grant; Modest; AHA SDG 14SDG18650010. M.E. Weber: None. X. Wang: None. K.M. Westfall: None. J. Viterna: None. M. Finucan: None. J. Kirsop: None. J. Kirsop: None. T. Engelman: None. P.L. Fox: None. S.L. Hazen: Other Research Support; Modest; Cleveland Heart Lab, Liposcience, Inc., Proctor & Gamble, Takeda. Consultant/Advisory Board; Modest; AstraZeneca Pharmaceuticals, BG Medicine, Inc., Cleveland Heart Lab, Esperion, Lilly, Liposcience, Inc., Merck & Co., Inc., Pfizer, Inc., Proctor & Gamble, Takeda. Other; Modest; Cleveland Heart Lab., Frantz Biomarkers, LLC, Liposcience, Inc.. W. Tang: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.