Abstract
A role for myeloperoxidase (MPO) in atherosclerosis has received considerable attention recently. To identify potential chlorinated lipid products in human low density lipoprotein (LDL), studies were designed to demonstrate that MPO-derived reactive chlorinating species (RCS) target the plasmalogen pool of LDL isolated from peripheral human blood in vitro. The vinyl ether bond of LDL plasmalogens was targeted by MPO-derived RCS, resulting in the release of the 16- and 18-carbon-containing alpha-chloro fatty aldehydes, 2-chlorohexadecanal and 2-chlorooctadecanal, respectively, from the plasmalogen glycerol backbone. Targeting of the LDL plasmalogen vinyl ether bond was dependent on the presence of MPO-derived RCS. Electrospray ionization mass spectrometric analysis of MPO-treated LDL demonstrated that a novel population of unsaturated lysophosphatidylcholine molecular species was produced by a phospholipase A2-independent mechanism. Unsaturated lysophosphatidylcholine molecular species elicited cyclic AMP response element binding protein phosphorylation in RAW 264.7 cells. Additionally, MPO-mediated targeting of both monocyte and LDL plasmalogen pools was demonstrated in phorbol myristate acetate-stimulated human monocytes, resulting in the production of both 2-chlorohexadecanal and 2-chlorooctadecanal. In contrast, alpha-chloro fatty aldehydes were not produced in phorbol myristate acetate-stimulated mouse monocytes. Collectively, the present studies demonstrate a novel MPO-specific mechanism that mediates the production of a novel group of unsaturated lysophosphatidylcholine molecular species and chlorinated aldehydes from both LDL and monocyte plasmalogen pools that may have important effects during inflammatory reactions mediated by monocytes, most notably atherosclerosis.
Highlights
Myeloperoxidase (MPO),1 a bactericidal enzyme secreted by activated phagocytes, catalyzes the production of Atherosclerosis is an inflammatory arterial pathology occurring most significantly in coronary and carotid arteries
The present findings demonstrate that human low density lipoprotein (LDL) plasmalogens are attacked by MPO-derived reactive chlorinating species (RCS), resulting in the production of ␣-chloro fatty aldehydes as well as unsaturated lysophosphatidylcholine (LPC) molecular species
To determine that MPO-derived RCS target LDL plasmalogens, human LDL isolated from peripheral blood was incubated with RCS generated from MPO, and lipidic products were converted to their PFB oxime derivatives and subjected to negative ion chemical ionization (NICI) gas chromatography-mass spectrometry (GC-MS) analysis
Summary
Myeloperoxidase (MPO),1 a bactericidal enzyme secreted by activated phagocytes, catalyzes the production of Atherosclerosis is an inflammatory arterial pathology occurring most significantly in coronary and carotid arteries. The present studies demonstrate a novel MPO-specific mechanism that mediates the production of a novel group of unsaturated lysophosphatidylcholine molecular species and chlorinated aldehydes from both LDL and monocyte plasmalogen pools that may have important effects during inflammatory reactions mediated by monocytes, most notably atherosclerosis.
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