Abstract 19686: Cardioprotective Role of Paraoxonases in Heart Failure
Paraoxonases isoforms 1, 2, and 3 (PON-1, -2, -3) constitute a family of calcium-dependent esterases which exhibit arylesterase, paraoxonase, and lactonase activities. Decreased serum PON activity is associated with increased oxidant stress and adverse clinical outcomes in the setting of heart failure (HF), yet whether decreased PON is mechanistically linked to HF is unclear. We tested the hypothesis that PON is cardioprotective in the following studies. First we measured PON expression in explanted human hearts. Both PON2 and PON3 protein and mRNA levels were significantly higher (>2 fold, p<0.05). Next, we measured PON myocardial lactonase activity in the explanted hearts. Despite the significant increase in myocardial PON expression in HF patients, myocardial lactonase activity was significantly lower in heart tissue homogenates of patients with dilated cardiomyopathy (24% decreased, p<0.05) or ischemic cardiomyopathy (36% decreased, p<0.01) compared to non-HF control hearts. Next, we performed left anterior descending coronary artery ligation (LADx) on wild type (WT), PON2-/- and PON3-/- knock-out mice. PON myocardial lactonase activity was significantly lower in heart tissues homogenates of PON2-/- and PON3-/- mice compared to WT. Four weeks after LADx, PON2-/- and PON3-/- mice demonstrated increased myocardial fibrosis compared to WT (Figure). These studies suggest a cardioprotective role for PON in HF.
Author Disclosures: D.J. Kennedy: Research Grant; Modest; AHA SDG 14SDG18650010. M.E. Weber: None. K.M. Westfall: None. X. Wang: None. D. Shih: None. S.T. Reddy: None. A.J. Lusis: None. S.L. Hazen: Other Research Support; Modest; Cleveland Heart Lab, Liposcience, Inc., Proctor & Gamble, Takeda. Ownership Interest; 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.