Myeloperoxidase (MPO) and MPO-derived products have been detected in human atherosclerotic lesions. We have recently demonstrated that MPO-derived, reactive chlorinating species (RCS) target the vinyl ether bond of tissue plasmalogens resulting in the production of alpha-chloro-fatty aldehyde (alpha-CI-FALD), and unsaturated molecular species of lysophosphatidylcholine (UnsatLPC). Furthermore, preliminary studies show that alpha-CI-FALD and UnsatLPC are present in human atherosclerotic lesions. In addition to alpha-CI-FALD and UnsatLPC, preliminary studies have demonstrated that attack of the plasmalogen vinyl ether bond by MPO-derived RCS can yield: 1) intact plasmalogens that are chlorinated across the vinyl ether bond; 2) alkyl ether phospholipids (i.e., precursors of platelet activating factor, PAF); 3) lysophosphatidylcholine molecular species containing chlorohydrins; 4) phosphatidylethanolamine molecular species containing alpha-CI-FALD-N-modified ethanolamine polar head groups; and 5) alpha-CI-FALD-N-modified peptides. The potential biological role of these RCS-derived plasmalogen oxidation products is suggested by preliminary data showing that they are chemoattractants, alter gene transcription and elicit both COX-2 and iNOS expression as well as endothelial cell surface expression of P-selectin. These preliminary findings have led to the hypothesis that the targeting of tissue and lipoprotein plasmalogens by RCS is a biochemical mechanism responsible for the generation of a novel family of lipidic mediators of atherosclerosis. This hypothesis will be tested by the following specific aims: The goals of Aim 1 are to identify the RCS-derived plasmalogen oxidation products in human atherosclerotic lesions and in tissues targeted by activated monocytes and macrophages. The goals of Aim 2 are to demonstrate that plasmalogen attack by RCS is an important biochemical mechanism that produces lipidic mediators that are proatherogenic. The goals of Aim 3 are to determine the role of RCS-derived plasmalogen oxidation products on cell proliferation and death.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Metabolism Study Section (MET)
Program Officer
Wassef, Momtaz K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Saint Louis University
Schools of Medicine
Saint Louis
United States
Zip Code
Palladino, Elisa N D; Wang, Wen-Yi; Albert, Carolyn J et al. (2017) Peroxisome proliferator-activated receptor-? accelerates ?-chlorofatty acid catabolism. J Lipid Res 58:317-324
Wang, Bo; Rong, Xin; Duerr, Mark A et al. (2016) Intestinal Phospholipid Remodeling Is Required for Dietary-Lipid Uptake and Survival on a High-Fat Diet. Cell Metab 23:492-504
Rong, Xin; Wang, Bo; Dunham, Merlow M et al. (2015) Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion. Elife 4:
Duerr, Mark A; Aurora, Rajeev; Ford, David A (2015) Identification of glutathione adducts of ?-chlorofatty aldehydes produced in activated neutrophils. J Lipid Res 56:1014-24
Aroor, Annayya R; Habibi, Javad; Ford, David A et al. (2015) Dipeptidyl peptidase-4 inhibition ameliorates Western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function. Diabetes 64:1988-2001
Shih, Diana M; Yu, Janet M; Vergnes, Laurent et al. (2015) PON3 knockout mice are susceptible to obesity, gallstone formation, and atherosclerosis. FASEB J 29:1185-97
Soufi, Nisreen; Hall, Angela M; Chen, Zhouji et al. (2014) Inhibiting monoacylglycerol acyltransferase 1 ameliorates hepatic metabolic abnormalities but not inflammation and injury in mice. J Biol Chem 289:30177-88
Baldan, Angel; Gonen, Ayelet; Choung, Christina et al. (2014) ABCG1 is required for pulmonary B-1 B cell and natural antibody homeostasis. J Immunol 193:5637-48
Yang, Yanbo; Kuwano, Takashi; Lagor, William R et al. (2014) Lipidomic analyses of female mice lacking hepatic lipase and endothelial lipase indicate selective modulation of plasma lipid species. Lipids 49:505-15
Shao, Fei; Ford, David A (2014) Elaidic acid increases hepatic lipogenesis by mediating sterol regulatory element binding protein-1c activity in HuH-7 cells. Lipids 49:403-13

Showing the most recent 10 out of 44 publications