Abstract 18299: De Novo Leukotriene B4 Production From High-Density Lipoprotein (HDL) in Recurrent Cardiovascular Disease Patients Deteriorates Anti-Inflammatory Properties of HDL
Introduction: We recently reported that serum myeloperoxidase/paraoxonase 1 (MPO/PON1) ratio could be used as a useful marker for high density lipoprotein (HDL) function and elevated MPO/PON1 ratio correlated to recurrent cardiovascular diseases. We hypothesized that HDL from high MPO/PON1 ratio cases (high MPO/PON1 HDL) might have specific bioactive molecules which contributed dysfunctional HDL and atherosclerotic diseases.
Methods and Results: HDL was purified by ultracentrifuge from cases with various MPO/PON1 ratios. Comprehensive liquid chromatography/mass spectrometry (LC/MS) based lipid mediator analysis revealed that high MPO/PON1 HDL produced potent pro-inflammatory lipid mediator, leukotriene B4 (LTB4). We also found that high MPO/PON1 HDL carried higher MPO, lower PON1, as well as abundant LTB4 producing enzymes, 5-lipoxygenase (5-LO) and LTA4 hydrolase.
To investigate biological impact of HDL on activated macrophages, lipid mediator productions from activated macrophages were analyzed with HDL treatment. Low MPO/PON1 HDL treatment attenuated pro-inflammatory lipid mediator production from macrophages, especially LTB4. We found that low MPO/PON1 HDL enhanced proteasome-mediated degradation of 5-LO in activated macrophages. However, high MPO/PON1 HDL failed to reduce 5-LO in macrophages. Consequently, activated macrophages maintained pro-inflammatory properties with high MPO/PON1 HDL treatment. As the mechanisms, low MPO/PON1 HDL, but not high MPO/PON1 HDL, was transferred into macrophages via clathrin-mediated endocytosis. HDL endocytosis seems to be a critical step for their anti-inflammatory properties, as endocytosis inhibitor Pitstop2 abolished 5-LO degradation in macrophages by HDL. nM range of LTB4 completely attenuated HDL endocytosis into macrophages, indicating that LTB4 produced from high MPO/PON1 HDL might play critical roles in dysfunctional, inflammatory HDL characteristics.
Conclusions: Recurrent cardiovascular disease patients have elevated MPO/PON1 ratio in serum as well as in HDL. High MPO/PON1 HDL produces pro-inflammatory LTB4, which attenuates endocytotic HDL uptake into macrophages, fails to reduce proinflammatory lipid mediator production from activated macrophages.
Author Disclosures: S. Tsuda: None. M. Shinohara: None. T. Oshita: None. M. Nagao: None. N. Tanaka: None. T. Mori: None. T. Hara: None. Y. Irino: None. R. Toh: None. T. Ishida: None. K. Hirata: None.
- © 2016 by American Heart Association, Inc.